COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition.
COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition.
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DOI：
10.1016/j.biopsych.2011.12.023
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发表时间：
2012-03-15
影响因子：
10.6
通讯作者：
Harrison, Paul J.
中科院分区：
文献类型：
--
作者：
Farrell, Sarah M.;Tunbridge, Elizabeth M.;Braeutigam, Sven;Harrison, Paul J.
儿茶酚-O-甲基转移酶（COMT）代谢多巴胺。COMT Val 158 Met多态性影响其活性，并且已经报道了该基因型对多巴胺能表型，特别是工作记忆的多种神经相关性。COMT活性也可通过COMT抑制剂间接调节。皮质多巴胺信号和工作记忆之间的倒U型关系预测，COMT抑制的效果将根据COMT基因型而不同。34名COMT Met 158 Met（Met-COMT）和33名COMT Val 158 Val（Val-COMT）男性在一项随机、双盲、受试者间设计中接受单次200 mg剂量的脑渗透性COMT抑制剂托卡朋或安慰剂。他们完成了工作记忆的N-back任务和赌博任务。在安慰剂组中，Met-COMT受试者在2- back上的表现优于Val-COMT受试者，并且他们更厌恶风险。托卡朋在两个基因型组中具有相反的作用：它使Met-COMT受试者的N-back表现恶化，但在Val-COMT受试者中增强。托卡朋使Met-COMT受试者的风险厌恶程度降低，但Val-COMT受试者的风险厌恶程度更高。在这两项任务中，托卡朋逆转了基线基因型差异。根据基因型，COMT抑制可以增强或损害工作记忆，增加或减少风险决策。据我们所知，这些数据是迄今为止最清楚的证明，即药物的作用方向可以受到其靶基因多态性的影响。结果支持多巴胺功能的倒U模型。这些发现具有翻译相关性，因为COMT抑制剂用于帕金森病的连续治疗，并正在评估精神分裂症和其他疾病。
Catechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val158Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype. Thirty-four COMT Met158Met (Met-COMT) and 33 COMT Val158Val (Val-COMT) men were given a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. They completed the N-back task of working memory and a gambling task. In the placebo group, Met-COMT subjects outperformed Val-COMT subjects on the 2- back, and they were more risk averse. Tolcapone had opposite effects in the two genotype groups: it worsened N-back performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Tolcapone made Met-COMT subjects less risk averse but Val-COMT subjects more so. In both tasks, tolcapone reversed the baseline genotype differences. Depending on genotype, COMT inhibition can enhance or impair working memory and increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders.
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DOI：
10.1073/pnas.111134598
发表时间：
2001-06-05
影响因子：
11.1
作者：
Egan, MF;Goldberg, TE;Weinberger, DR
通讯作者：
Weinberger, DR
影响因子：
10.6
作者：
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通讯作者：
D'Esposito, Mark
影响因子：
10.6
作者：
Barnett, Jennifer H.;Scoriels, Linda;Munafo, Marcus R.
通讯作者：
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影响因子：
56.9
作者：
Gehring, WJ;Willoughby, AR
通讯作者：
Willoughby, AR
影响因子：
7.6
作者：
Callicott, JH;Ramsey, NF;Weinberger, DR
通讯作者：
Weinberger, DR