Division of Medical Psychology, Department of Psychiatry and Psychotherapy, University Hospital Bonn, 53105 Bonn, Germany.
Department of Psychiatry, School of Medicine & Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany.
Proc Natl Acad Sci U S A. 2020 May 26;117(21):11781-11787. doi: 10.1073/pnas.1920147117. Epub 2020 May 8.
Benzodiazepines (BZDs) represent the gold standard of anxiolytic pharmacotherapy; however, their clinical benefit is limited by side effects and addictive potential. Consequently, there is an urgent need to develop novel and safe anxiolytics. The peptide hormone oxytocin (OXT) exhibits anxiolytic-like properties in animals and humans, but whether OXT and BZDs share similar effects on the neural circuitry of fear is unclear. Therefore, the rationale of this ultra-high-field functional MRI (fMRI) study was to test OXT against the clinical comparator lorazepam (LZP) with regard to their neuromodulatory effects on local and network responses to fear-related stimuli. One hundred twenty-eight healthy male participants volunteered in this randomized double-blind, placebo-controlled, between-group study. Before scanning using an emotional face-matching paradigm, participants were randomly administered a single dose of OXT (24 IU), LZP (1 mg), or placebo. On the behavioral level, LZP, but not OXT, caused mild sedation, as evidenced by a 19% increase in reaction times. On the neural level, both OXT and LZP inhibited responses to fearful faces vs. neutral faces within the centromedial amygdala (cmA). In contrast, they had different effects on intra-amygdalar connectivity; OXT strengthened the coupling between the cmA and basolateral amygdala, whereas LZP increased the interplay between the cmA and superficial amygdala. Furthermore, OXT, but not LZP, enhanced the coupling between the cmA and the precuneus and dorsomedial prefrontal cortex. These data implicate inhibition of the cmA as a common denominator of anxiolytic action, with only OXT inducing large-scale connectivity changes of potential therapeutic relevance.
苯二氮䓬类药物（BZDs）是抗焦虑药物治疗的金标准；然而，它们的临床疗效受到副作用和成瘾潜力的限制。因此，迫切需要开发新型和安全的抗焦虑药物。神经肽激素催产素（OXT）在动物和人类中表现出抗焦虑样特性，但 OXT 和 BZDs 是否对恐惧相关刺激的神经回路具有相似的作用尚不清楚。因此，这项超高场功能磁共振成像（fMRI）研究的基本原理是测试 OXT 与临床对照药物劳拉西泮（LZP）在其对恐惧相关刺激的局部和网络反应的神经调节作用方面的差异。128 名健康男性志愿者参与了这项随机、双盲、安慰剂对照、分组研究。在使用情绪面孔匹配范式进行扫描之前，参与者被随机给予单剂量 OXT（24IU）、LZP（1mg）或安慰剂。在行为水平上，LZP 而非 OXT 导致轻微镇静，表现在反应时间增加了 19%。在神经水平上，OXT 和 LZP 均抑制了中央杏仁核（cmA）内对恐惧面孔和中性面孔的反应。相比之下，它们对杏仁内连接有不同的影响；OXT 增强了 cmA 和基底外侧杏仁核之间的耦合，而 LZP 增加了 cmA 和浅层杏仁核之间的相互作用。此外，OXT 而非 LZP 增强了 cmA 与楔前叶和背内侧前额叶皮层之间的耦合。这些数据表明，抑制 cmA 是抗焦虑作用的共同基础，只有 OXT 诱导具有潜在治疗相关性的大规模连接变化。
