Clinical Hospital of Chengdu Brain Science Institute and Ministry of Education (MOE) Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China.
Faculty of Psychology, Southwest University, Chongqing, China; Key Laboratory of Cognition and Personality, Ministry of Education, Southwest University, Chongqing, China.
Biol Psychiatry. 2019 Dec 15;86(12):910-920. doi: 10.1016/j.biopsych.2019.07.007. Epub 2019 Jul 25.
Deficient extinction learning and threat adaptation in the ventromedial prefrontal cortex (vmPFC)-amygdala circuitry strongly impede the efficacy of exposure-based interventions in anxiety disorders. Recent animal models suggest a regulatory role of the renin-angiotensin system in both these processes. Against this background, the present randomized placebo-controlled pharmacologic functional magnetic resonance imaging experiment aimed at determining the extinction enhancing potential of the angiotensin II type 1 receptor antagonist losartan (LT) in humans.
Seventy healthy male subjects underwent Pavlovian threat conditioning and received single-dose LT (50 mg) or placebo administration before extinction. Psychophysiological threat reactivity (skin conductance response) and neural activity during extinction served as primary outcomes. Psychophysiological interaction, voxelwise mediation, and novel multivariate pattern classification analyses were used to determine the underlying neural mechanisms.
LT significantly accelerated the decline of the psychophysiological threat response during within-session extinction learning. On the neural level, the acceleration was accompanied and critically mediated by threat-specific enhancement of vmPFC activation. Furthermore, LT enhanced vmPFC-basolateral amygdala coupling and attenuated the neural threat expression, particularly in the vmPFC, during early extinction.
Overall the results indicate that LT facilitates within-session threat memory extinction by augmenting threat-specific encoding in the vmPFC and its regulatory control over the amygdala. The findings document a pivotal role of angiotensin regulation of extinction learning in humans and suggest that adjunct LT administration has the potential to facilitate the efficacy of exposure-based interventions in anxiety disorders.
腹内侧前额皮质（vmPFC）-杏仁核回路中缺乏消退学习和威胁适应能力，强烈阻碍了暴露疗法在焦虑障碍中的疗效。最近的动物模型表明肾素-血管紧张素系统（renin-angiotensin system）在这两个过程中都具有调节作用。在此背景下，本项随机安慰剂对照药物功能磁共振成像实验旨在确定血管紧张素 II 型 1 型受体拮抗剂氯沙坦（LT）对人类的增强消退作用。
70 名健康男性被试接受了条件性恐惧学习，并在消退前接受单次 LT（50mg）或安慰剂给药。消退过程中的心理生理威胁反应（皮肤电反应）和神经活动作为主要结果。使用心理生理交互作用、体素水平中介分析和新的多变量模式分类分析来确定潜在的神经机制。
LT 显著加速了单次治疗期间内消退学习过程中心理生理威胁反应的下降。在神经水平上，这种加速伴随着并由 vmPFC 激活的特定威胁增强来介导。此外，LT 增强了 vmPFC-基底外侧杏仁核的耦合，并在早期消退期间减轻了神经威胁表达，特别是在 vmPFC 中。
总体而言，结果表明 LT 通过增强 vmPFC 中特定威胁的编码以及对杏仁核的调节控制，促进了单次治疗期间的威胁记忆消退。这些发现证明了血管紧张素对人类消退学习的调节作用的关键作用，并表明 LT 的辅助给药有可能提高焦虑障碍中暴露疗法的疗效。
