Divergent Effects of Genetic Variation in Endocannabinoid Signaling on Human Threat- and Reward-Related Brain Function
Divergent Effects of Genetic Variation in Endocannabinoid Signaling on Human Threat- and Reward-Related Brain Function
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DOI：
10.1016/j.biopsych.2008.10.047
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发表时间：
2009-07-01
影响因子：
10.6
通讯作者：
Manuck, Stephen B.
中科院分区：
文献类型：
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作者：
Hariri, Ahmad R.;Gorka, Adam;Manuck, Stephen B.
背景：脂肪酸酰胺水解酶(FAAH)是调节内源性大麻素(ECB)信号的关键酶。结果：与C385纯合子相比，FAAH385A基因携带者与威胁相关的杏仁核反应性降低，而与奖赏相关的纹状体腹侧反应性增加。同样，FAAHC385A基因在脑-行为关系水平上也表现出不同的效应。385A携带者的杏仁核反应性与特质焦虑之间的相关性降低，而腹侧纹状体反应性与冲动指数延迟折扣之间的相关性增加。结论：我们的结果平行于对ECB信号的药理学和遗传学剖析，与Delta(9)-四氢大麻酚的精神作用一致，并强调了ECB信号的变异性影响与成瘾和肥胖风险相关的复杂行为过程的特定神经机制。
Background: Fatty acid amide hydrolase (FAAH) is a key enzyme in regulating endocannabinoid (eCB) signaling. A common single nucleotide polymorphism (C385A) in the human FAAH gene has been associated with increased risk for addiction and obesity.Methods: Using imaging genetics in 82 healthy adult volunteers, we examined the effects of FAAH C385A on threat- and reward-related human brain function.Results: Carriers of FAAH 385A, associated with reduced enzyme and possibly increased eCB signaling, had decreased threat-related amygdala reactivity but increased reward-related ventral striatal reactivity in comparison with C385 homozygotes. Similarly divergent effects of FAAH C385A genotype were manifest at the level of brain-behavior relationships. The 385A carriers showed decreased correlation between amygdala reactivity and trait anxiety but increased correlation between ventral striatal reactivity and delay discounting, an index of impulsivity.Conclusions: Our results parallel pharmacologic and genetic dissection of eCB signaling, are consistent with the psychotropic effects of Delta(9)-tetrahydrocannabinol, and highlight specific neural mechanisms through which variability in eCB signaling impacts complex behavioral processes related to risk for addiction and obesity.