Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity.
Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity.
复制标题
DOI：
10.1038/mp.2012.72
复制
发表时间：
2013-07
影响因子：
11
通讯作者：
Holmes, A.
中科院分区：
文献类型：
--
作者：
Gunduz-Cinar, O.;MacPherson, K. P.;Cinar, R.;Gamble-George, J.;Sugden, K.;Williams, B.;Godlewski, G.;Ramikie, T. S.;Gorka, A. X.;Alapafuja, S. O.;Nikas, S. P.;Makriyannis, A.;Poulton, R.;Patel, S.;Hariri, A. R.;Caspi, A.;Moffitt, T. E.;Kunos, G.;Holmes, A.
内源性大麻素根据生理需要按需释放，并可通过抑制其分解代谢降解来增强。内源性大麻素anandamide被分解代谢酶脂肪酸酰胺水解酶（FAAH）降解。大麻素参与了恐惧行为的调节，包括恐惧消退，这表明选择性地提高大脑大麻素可以调节恐惧的可塑性变化。在这里，我们首先测试了这一假设的临床前实验采用一种新的，有效的和选择性的FAAH抑制剂，AM3506（5-（4-羟基苯基）戊磺酰氟）。在消退受损的小鼠模型中，消退前全身性AM3506给药降低了恢复测试期间的恐惧。AM3506在没有灭绝训练的情况下对恐惧没有影响，也没有对各种非恐惧相关的措施产生影响。基底外侧杏仁核中的Anandamide水平通过消退训练增加，并通过全身性AM3506增强，而AM3506对杏仁核切片的应用促进了抑制性传递的长期抑制，这是一种与消退相关的突触可塑性形式。进一步支持杏仁核作为效应位点，全身性AM3506的减轻恐惧的作用被CB 1受体拮抗剂的杏仁核内输注阻断，并且被AM3506的杏仁核内输注完全重现。基于这些临床前研究结果，我们假设人类FAAH基因的变异可以预测杏仁核威胁处理和压力应对特征的个体差异。与此相一致的是，低表达FAAH变体（385 A等位基因; rs324420）的携带者表现出更快的杏仁核对威胁的习惯性反应，并且在压力反应的人格特质上得分较低。我们的研究结果表明，增加杏仁核anandamide能够减少小鼠的恐惧，并可能促进人类的压力应对。
Endocannabinoids are released ‘on-demand’ on the basis of physiological need, and can be pharmacologically augmented by inhibiting their catabolic degradation. The endocannabinoid anandamide is degraded by the catabolic enzyme fatty acid amide hydrolase (FAAH). Anandamide is implicated in the mediation of fear behaviors, including fear extinction, suggesting that selectively elevating brain anandamide could modulate plastic changes in fear. Here we first tested this hypothesis with preclinical experiments employing a novel, potent and selective FAAH inhibitor, AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride). Systemic AM3506 administration before extinction decreased fear during a retrieval test in a mouse model of impaired extinction. AM3506 had no effects on fear in the absence of extinction training, or on various non-fear-related measures. Anandamide levels in the basolateral amygdala were increased by extinction training and augmented by systemic AM3506, whereas application of AM3506 to amygdala slices promoted long-term depression of inhibitory transmission, a form of synaptic plasticity linked to extinction. Further supporting the amygdala as effect-locus, the fear-reducing effects of systemic AM3506 were blocked by intra-amygdala infusion of a CB1 receptor antagonist and were fully recapitulated by intra-amygdala infusion of AM3506. On the basis of these preclinical findings, we hypothesized that variation in the human FAAH gene would predict individual differences in amygdala threat-processing and stress-coping traits. Consistent with this, carriers of a low-expressing FAAH variant (385A allele; rs324420) exhibited quicker habituation of amygdala reactivity to threat, and had lower scores on the personality trait of stress-reactivity. Our findings show that augmenting amygdala anandamide enables extinction-driven reductions in fear in mouse and may promote stress-coping in humans.
登录
查看更多内容
DOI：
10.1523/jneurosci.4904-07.2008
发表时间：
2008-08-06
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hefner K;Whittle N;Juhasz J;Norcross M;Karlsson RM;Saksida LM;Bussey TJ;Singewald N;Holmes A
通讯作者：
Holmes A
影响因子：
3.3
作者：
Alvares, L. De Oliveira;Genro, B. Pasqualini;Quillfeldt, J. A.
通讯作者：
Quillfeldt, J. A.
影响因子：
4.2
作者：
Brown, Sarah M.;Manuck, Stephen B.;Hariri, Ahmad R.
通讯作者：
Hariri, Ahmad R.
影响因子：
7.6
作者：
Kamprath, Kornelia;Romo-Parra, Hector;Pape, Hans-Christian
通讯作者：
Pape, Hans-Christian
影响因子：
5.3
作者：
Flanagan, Jonathan M.;Gerber, Alexandra L.;Sipe, Jack C.
通讯作者：
Sipe, Jack C.