Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor

Maria P. Arolfo, David H. Overstreet, Lina Yao, Peidong Fan, Andrew J. Lawrence, Guoxin Tao, Wing Ming Keung, Bert L. Vallee, Michael Olive, Justin T. Gass, Emanuel Rubin, Helen Anni, Clyde W. Hodge, Joyce Besheer, Jeff Zablocki, Kwan Leung, Brent K. Blackburn, Louis G. Lange, Ivan Diamond

Research output: Contribution to journalArticle

57 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1935-1944
Number of pages10
JournalAlcoholism: Clinical and Experimental Research
Volume33
Issue number11
DOIs
StatePublished - Nov 2009
Externally publishedYes

Fingerprint

Aldehyde Dehydrogenase
Alcohol Drinking
Drinking
Alcohols
Acetaldehyde
Rats
Nucleus Accumbens
Pueraria
Dopamine
Alcoholism
Rodentia
Bottles
Self Administration
Cues
Recurrence
Plant Extracts
Chinese Traditional Medicine
Alcoholics
Medicine
Blood

Keywords

  • Acetaldehyde
  • Alcohol
  • ALDH-2 Inhibitor
  • Dopamine
  • Rat

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

Cite this

Arolfo, M. P., Overstreet, D. H., Yao, L., Fan, P., Lawrence, A. J., Tao, G., ... Diamond, I. (2009). Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor. Alcoholism: Clinical and Experimental Research, 33(11), 1935-1944. https://doi.org/10.1111/j.1530-0277.2009.01031.x

Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor. / Arolfo, Maria P.; Overstreet, David H.; Yao, Lina; Fan, Peidong; Lawrence, Andrew J.; Tao, Guoxin; Keung, Wing Ming; Vallee, Bert L.; Olive, Michael; Gass, Justin T.; Rubin, Emanuel; Anni, Helen; Hodge, Clyde W.; Besheer, Joyce; Zablocki, Jeff; Leung, Kwan; Blackburn, Brent K.; Lange, Louis G.; Diamond, Ivan.

In: Alcoholism: Clinical and Experimental Research, Vol. 33, No. 11, 11.2009, p. 1935-1944.

Research output: Contribution to journalArticle

Arolfo, MP, Overstreet, DH, Yao, L, Fan, P, Lawrence, AJ, Tao, G, Keung, WM, Vallee, BL, Olive, M, Gass, JT, Rubin, E, Anni, H, Hodge, CW, Besheer, J, Zablocki, J, Leung, K, Blackburn, BK, Lange, LG & Diamond, I 2009, 'Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor', Alcoholism: Clinical and Experimental Research, vol. 33, no. 11, pp. 1935-1944. https://doi.org/10.1111/j.1530-0277.2009.01031.x
Arolfo, Maria P. ; Overstreet, David H. ; Yao, Lina ; Fan, Peidong ; Lawrence, Andrew J. ; Tao, Guoxin ; Keung, Wing Ming ; Vallee, Bert L. ; Olive, Michael ; Gass, Justin T. ; Rubin, Emanuel ; Anni, Helen ; Hodge, Clyde W. ; Besheer, Joyce ; Zablocki, Jeff ; Leung, Kwan ; Blackburn, Brent K. ; Lange, Louis G. ; Diamond, Ivan. / Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor. In: Alcoholism: Clinical and Experimental Research. 2009 ; Vol. 33, No. 11. pp. 1935-1944.
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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.",
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AU - Overstreet, David H.

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AU - Lawrence, Andrew J.

AU - Tao, Guoxin

AU - Keung, Wing Ming

AU - Vallee, Bert L.

AU - Olive, Michael

AU - Gass, Justin T.

AU - Rubin, Emanuel

AU - Anni, Helen

AU - Hodge, Clyde W.

AU - Besheer, Joyce

AU - Zablocki, Jeff

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AU - Blackburn, Brent K.

AU - Lange, Louis G.

AU - Diamond, Ivan

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N2 - 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.

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