Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1.
Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1.
复制标题
人类大麻素受体中未能消除恐惧和遗传变异性1。
DOI：
10.1038/tp.2012.90
复制
发表时间：
2012-09-25
影响因子：
6.8
通讯作者：
Baas JM
中科院分区：
文献类型：
--
作者：
Heitland I;Klumpers F;Oosting RS;Evers DJ;Leon Kenemans J;Baas JM
未能消除恐惧会导致持续的焦虑，并被认为是人类焦虑症发病机制的重要机制。在动物中，有充分证据表明，内源性大麻素系统在成功消除恐惧方面发挥着关键作用，最重要的是通过大麻素受体 1。然而，尚未有人类研究报道这一临床前证据的转化。健康的无药物受试者（N = 150）在虚拟现实环境中经历了恐惧调节和消除程序。测量眨眼惊吓反射的恐惧增强来评估恐惧条件反应，并收集主观恐惧评级。对参与者的大麻素受体 1 启动子区 (rs2180619) 和编码区 (rs1049353) 内的两个多态性进行了基因分型。正如临床前文献预测的那样，条件性恐惧的获得和表达在基因型之间没有差异。至关重要的是，rs2180619 的纯合子（G/G，N=23）和杂合子（A/G，N=68）G 等位基因携带者均表现出强烈的恐惧消退，而 A/A 纯合子（N=51）则不存在恐惧增强惊吓的消退。此外，这种对消除恐惧的抵抗使得 rs2180619 的 A/A 携带者在消除训练结束时具有明显更高水平的恐惧增强惊吓。没有观察到 rs1049353 基因型对恐惧获得和消退的影响。这些结果首次表明人类内源性大麻素系统参与恐惧消退。这意味着该系统的遗传变异可能是焦虑个体差异的基础，使大麻素受体 1 成为焦虑症新型药物治疗的潜在靶点。
Failure to extinguish fear can lead to persevering anxiety and has been postulated as an important mechanism in the pathogenesis of human anxiety disorders. In animals, it is well documented that the endogenous cannabinoid system has a pivotal role in the successful extinction of fear, most importantly through the cannabinoid receptor 1. However, no human studies have reported a translation of this preclinical evidence yet. Healthy medication-free human subjects (N=150) underwent a fear conditioning and extinction procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex was measured to assess fear-conditioned responding, and subjective fear ratings were collected. Participants were genotyped for two polymorphisms located within the promoter region (rs2180619) and the coding region (rs1049353) of cannabinoid receptor 1. As predicted from the preclinical literature, acquisition and expression of conditioned fear did not differ between genotypes. Crucially, whereas both homozygote (G/G, N=23) and heterozygote (A/G, N=68) G-allele carriers of rs2180619 displayed robust extinction of fear, extinction of fear-potentiated startle was absent in A/A homozygotes (N=51). Additionally, this resistance to extinguish fear left A/A carriers of rs2180619 with significantly higher levels of fear-potentiated startle at the end of the extinction training. No effects of rs1049353 genotype were observed regarding fear acquisition and extinction. These results suggest for the first time involvement of the human endocannabinoid system in fear extinction. Implications are that genetic variability in this system may underlie individual differences in anxiety, rendering cannabinoid receptor 1 a potential target for novel pharmacological treatments of anxiety disorders.