The effects of FAAH inhibition on the neural basis of anxiety-related processing in healthy male subjects: a randomized clinical trial.
The effects of FAAH inhibition on the neural basis of anxiety-related processing in healthy male subjects: a randomized clinical trial.
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FAAH 抑制对健康男性受试者焦虑相关处理的神经基础的影响：一项随机临床试验。
DOI：
10.1038/s41386-020-00936-w
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Chaplan,SandraR
中科院分区：
文献类型：
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作者：
Paulus,MartinP;Stein,MurrayB;Simmons,AlanN;Risbrough,VictoriaB;Halter,Robin;Chaplan,SandraR
对 anandamide 降解酶脂肪酸酰胺水解酶 (FAAH) 的急性药理抑制可延长内源性大麻素的调节作用，并以大麻素受体依赖性方式逆转应激引起的焦虑状态。然而，人们对这种调节背后的神经系统知之甚少。对 43 名受试者进行了一项单中心、随机、双盲、安慰剂对照的平行研究，这些受试者被分配每天一次服用安慰剂 (n= 21) 或 JNJ-42165279 (100 mg) (n= 22)，连续 4 天。在给药最后一天评估药效学效果，包括在（1）情绪面部处理任务、（2）吸气呼吸负荷任务和（3）恐惧调节和消退任务期间使用 BOLD fMRI 评估大脑激活模式。 JNJ-42165279 在情绪面部处理任务期间减弱了杏仁核、双侧前扣带皮层和双侧岛叶的激活，这与之前使用抗焦虑药物观察到的效果一致。较高水平的 anandamide 与双侧前扣带回和左侧岛叶的较大衰减相关。 JNJ-42165279 增加了前扣带回、双侧前岛叶和右下额皮质在预期厌恶性内感受事件期间的激活。 JNJ-42165279 不影响恐惧调节或会话内消退学习，主观和神经回路水平上缺乏差异就证明了这一点。总而言之，这些结果支持这样的假设：该剂量的 JNJ-42165279 与现有的抗焦虑药物具有一些共同的作用，可以抑制对情绪刺激的反应，但不能抑制对条件性恐惧的反应。
Acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), prolongs the regulatory effects of endocannabinoids and reverses the stress-induced anxiety state in a cannabinoid receptor-dependent manner. However, the neural systems underlying this modulation are poorly understood. A single site, randomized, double-blind, placebo-controlled, parallel study was conducted with 43 subjects assigned to receive once daily dosing of either placebo (n= 21) or JNJ-42165279 (100 mg) (n= 22) for 4 consecutive days. Pharmacodynamic effects were assessed on the last day of dosing and included evaluation of brain activation patterns using BOLD fMRI during an (1) emotion face-processing task, (2) inspiratory breathing load task, and (3) fear conditioning and extinction task. JNJ-42165279 attenuated activation in the amygdala, bilateral anterior cingulate, and bilateral insula during the emotion face-processing task consistent with effects previously observed with anxiolytic agents. Higher levels of anandamide were associated with greater attenuation in bilateral anterior cingulate and left insula. JNJ-42165279 increased the activation during anticipation of an aversive interoceptive event in the anterior cingulate and bilateral anterior insula and right inferior frontal cortex. JNJ-42165279 did not affect fear conditioning or within-session extinction learning as evidenced by a lack of differences on a subjective and neural circuit level. Taken together, these results support the hypothesis that JNJ-42165279 at this dose shares some effects with existing anxiolytic agents in dampening response to emotional stimuli but not responses to conditioned fear.