Suppression of Heavy Drinking and Alcohol Seeking by a Selective ALDH-2 Inhibitor

Authors

  • Maria P. Arolfo,

    Search for more papers by this author
    • *

      These authors contributed equally to this research.

  • David H. Overstreet,

    Search for more papers by this author
    • *

      These authors contributed equally to this research.

  • Lina Yao,

    Search for more papers by this author
    • *

      These authors contributed equally to this research.

  • Peidong Fan,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • Andrew J. Lawrence,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • Guoxin Tao,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • Wing-Ming Keung,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • Bert L. Vallee,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • M. Foster Olive,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • Justin T. Gass,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • Emanuel Rubin,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • Helen Anni,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • Clyde W. Hodge,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • Joyce Besheer,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • Jeff Zablocki,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • Kwan Leung,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • Brent K. Blackburn,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • Louis G. Lange,

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author
  • Ivan Diamond

    1. CV Therapeutics (MPA, LY, PF, JZ, KL, BKB, LGL, ID), Palo Alto, California; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine (DHO, CWH, JB), Chapel Hill, North Carolina; Howard Florey Institute & Centre for Neuroscience, University of Melbourne (AJL), Melbourne, Vic., Australia; The Endowment for Research in Human Biology, Inc. (GT, WMK, BLV), Boston, Massachusetts; Medical University of South Carolina (MFO, JTG), Charleston, South Carolina; and Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University (ER, HA), Philadelphia, Pennsylvania.
    Search for more papers by this author

Reprint requests: Ivan Diamond, MD, CV Therapeutics, 3172 Porter Dr., Palo Alto, CA 94304; Fax: 650-384-8040; E-mail: ivan.diamond@cvt.com

Abstract

Background:  Inherited human aldehyde dehydrogenase 2 (ALDH-2) deficiency reduces the risk for alcoholism. Kudzu plants and extracts have been used for 1,000 years in traditional Chinese medicine to treat alcoholism. Kudzu contains daidzin, which inhibits ALDH-2 and suppresses heavy drinking in rodents. Decreased drinking due to ALDH-2 inhibition is attributed to aversive properties of acetaldehyde accumulated during alcohol consumption. However, daidzin can reduce drinking in some rodents without necessarily increasing acetaldehyde. Therefore, a selective ALDH-2 inhibitor might affect other metabolic factors involved in regulating drinking.

Methods:  Aldehyde dehydrogenase 2 inhibitors were synthesized based on the co-crystal structure of ALDH-2 and daidzin. We tested the efficacy of a highly selective reversible ALDH-2 inhibitor, CVT-10216, in models of moderate and high alcohol drinking rats. We studied 2-bottle choice and deprivation-induced drinking paradigms in Fawn Hooded (FH) rats, operant self-administration in Long Evans (LE), FH, and inbred P (iP) rats and in cue-induced reinstatement in iP rats. We also assayed blood acetaldehyde levels as well as dopamine (DA) release in the nucleus accumbens (NAc) and tested possible rewarding/aversive effects of the inhibitor in a conditioned place preference (CPP) paradigm.

Results:  CVT-10216 increases acetaldehyde after alcohol gavage and inhibits 2-bottle choice alcohol intake in heavy drinking rodents, including deprivation-induced drinking. Moreover, CVT-10216 also prevents operant self-administration and eliminates cue-induced reinstatement of alcohol seeking even when alcohol is not available (i.e., no acetaldehyde). Alcohol stimulates DA release in the NAc, which is thought to contribute to increased drinking and relapse in alcoholism. CVT-10216 prevents alcohol-induced increases in NAc DA without changing basal levels. CVT-10216 does not show rewarding or aversive properties in the CPP paradigm at therapeutic doses.

Conclusion:  Our findings suggest that selective reversible ALDH-2 inhibitors may have therapeutic potential to reduce excessive drinking and to suppress relapse in abstinent alcoholics.

Ancillary