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

被引：75

作者：

Arolfo, Maria P. ^{[1
]}

Overstreet, David H. ^{[2
]}

Yao, Lina ^{[1
]}

Fan, Peidong ^{[1
]}

Lawrence, Andrew J. ^{[3
,4
]}

Tao, Guoxin ^{[5
]}

Keung, Wing-Ming ^{[5
]}

Vallee, Bert L. ^{[5
]}

Olive, M. Foster ^{[6
]}

Gass, Justin T.

Rubin, Emanuel ^{[7
]}

Anni, Helen ^{[7
]}

Hodge, Clyde W. ^{[2
]}

Besheer, Joyce ^{[2
]}

Zablocki, Jeff ^{[1
]}

Leung, Kwan ^{[1
]}

Blackburn, Brent K. ^{[1
]}

Lange, Louis G. ^{[1
]}

Diamond, Ivan ^{[1
]}

机构：

[1] CV Therapeut, Palo Alto, CA 94304 USA

[2] Univ N Carolina, Sch Med, Bowles Ctr Alcohol Studies, Chapel Hill, NC USA

[3] Univ Melbourne, Howard Florey Inst, Melbourne, Vic, Australia

[4] Univ Melbourne, Ctr Neurosci, Melbourne, Vic, Australia

[5] Endowment Res Human Biol Inc, Boston, MA USA

[6] Med Univ S Carolina, Charleston, SC 29425 USA

[7] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA

来源：

ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH | 2009年 / 33卷 / 11期

关键词：

Alcohol; ALDH-2; Inhibitor; Acetaldehyde; Dopamine; Rat; MITOCHONDRIAL ALDEHYDE DEHYDROGENASE; SYRIAN GOLDEN-HAMSTERS; NUCLEUS-ACCUMBENS; PREFERRING RATS; ETHANOL-CONSUMPTION; ANIMAL-MODELS; ACETALDEHYDE; DOPAMINE; DISULFIRAM; DAIDZIN;

D O I：

10.1111/j.1530-0277.2009.01031.x

中图分类号：

R194 [卫生标准、卫生检查、医药管理];

学科分类号：

100404 [儿少卫生与妇幼保健学];

摘要：

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.

引用

页码：1935 / 1944

页数：10

共 43 条

[1]

Ethanol operant self-administration in rats is regulated by adenosine A2 receptors [J].