Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor.
Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor.
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DOI：
10.1111/j.1530-0277.2009.01031.x
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发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Diamond I
中科院分区：
文献类型：
--
作者：
Arolfo MP;Overstreet DH;Yao L;Fan P;Lawrence AJ;Tao G;Keung WM;Vallee BL;Olive MF;Gass JT;Rubin E;Anni H;Hodge CW;Besheer J;Zablocki J;Leung K;Blackburn BK;Lange LG;Diamond I
遗传性人类乙醛脱氢酶2（ALDH-2）缺乏可降低酗酒风险。葛根植物和提取物在传统中医中用于治疗酒精中毒已有1,000年的历史。葛根含有大豆苷，它抑制ALDH-2和抑制啮齿动物的大量饮酒。由于ALDH-2抑制而导致的饮酒减少归因于饮酒过程中积累的乙醛的厌恶性质。然而，大豆苷可以减少一些啮齿动物的饮酒量，而不一定会增加乙醛。因此，选择性ALDH-2抑制剂可能会影响其他参与调节饮酒的代谢因素。利用乙醛脱氢酶-2（ALDH-2）与大豆苷的共晶结构，合成了乙醛脱氢酶-2（ALDH-2）抑制剂。我们在中度和高度饮酒大鼠模型中测试了高度选择性可逆ALDH-2抑制剂CVT-10216的疗效。我们在Fawn Hooded（FH）大鼠中研究了2瓶选择和剥夺诱导的饮水模式，在Long Evans（LE）、FH和近交系P（iP）大鼠中研究了操作性自我给药，以及在iP大鼠中研究了线索诱导的恢复。我们还测定了血液乙醛水平以及多巴胺（DA）的释放在丘脑核（NAc）和测试可能的奖励/厌恶的抑制剂在条件性位置偏爱（CPP）的范例。CVT-10216增加酒精灌胃后的乙醛，并抑制重度饮酒啮齿动物的2瓶选择酒精摄入，包括剥夺诱导的饮酒。此外，CVT-10216还防止操作性自我给药并消除线索诱导的酒精寻求恢复，即使在酒精不可用时（即，无乙醛）。酒精刺激NAc中的DA释放，这被认为有助于增加饮酒和酗酒复发。CVT-10216防止酒精诱导的NAc DA增加，而不改变基础水平。CVT-10216在治疗剂量下在CPP范例中不显示奖励或厌恶性质。我们的研究结果表明，选择性可逆ALDH-2抑制剂可能具有治疗潜力，以减少过度饮酒和抑制戒酒者的复发。[2009年8月10日在线发布后添加更正。]请参阅李廷凯博士对本文的相关评论，该评论将于2009年11月在线发表，并在第34期：1中出版。
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. 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. 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. Our findings suggest that selective reversible ALDH-2 inhibitors may have therapeutic potential to reduce excessive drinking and to suppress relapse in abstinent alcoholics. [Correction added after online publication 10 August 2009.] Please see the related Commentary to this article by Dr. Ting-Kai Li, which will appear online in November 2009 and in print in issue 34:1.
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DOI：
10.1073/pnas.90.21.10008
发表时间：
1993-11-01
影响因子：
11.1
作者：
KEUNG, WM;VALLEE, BL
通讯作者：
VALLEE, BL
DOI：
10.1124/jpet.105.090449
发表时间：
2005-11-01
影响因子：
3.5
作者：
Cowen, MS;Djouma, E;Lawrence, AJ
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Lawrence, AJ
DOI：
10.1073/pnas.92.19.8990
发表时间：
1995-09-12
影响因子：
11.1
作者：
KEUNG, WM;LAZO, O;VALLEE, BL
通讯作者：
VALLEE, BL
影响因子：
3.8
作者：
BRADY, JF;XIAO, F;YANG, CS
通讯作者：
YANG, CS
影响因子：
3.6
作者：
Cichelli, MJ;Lewis, MJ
通讯作者：
Lewis, MJ