D-cycloserine (DCS), a partial NMDA-receptor agonist, seems to be a promising enhancer for exposure therapy in anxiety disorders. It has been tested successfully in animal models of fear extinction, where DCS enhanced extinction learning. Applied in clinical studies, results of DCS-augmented exposure therapy remain ambiguous, calling for a deeper understanding of the underlying mechanisms of DCS and its exact effect on extinction learning and return of fear (ROF) in humans. In the present study, we investigated the effect of DCS-augmented extinction learning on behavioral, psychophysiological, and neural indices of ROF during a 24-h delayed recall test. Thirty-seven participants entered a randomized, placebo-controlled, double-blind, 3-day fear conditioning and delayed extinction fMRI design. One hour before extinction training, participants received an oral dose of 50 mg of DCS or a placebo. Behavioral arousal ratings revealed a generalized ROF during extinction recall in the placebo but not DCS group. Furthermore, participants receiving DCS compared to placebo showed attenuated differential BOLD responses in left posterior hippocampus and amygdala from extinction learning to extinction recall, due to increased hippocampal recruitment in placebo and trendwise decreased amygdala responding in DCS subjects. Our finding that DCS reduces ROF in arousal ratings and neural structures subserving defensive reactions support a role for NMDA receptors in extinction memory consolidation and encourage further translational research.

中文翻译：

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使用 D-环丝氨酸增强消退学习可减少恐惧的回归：一项随机、安慰剂对照的功能磁共振成像研究。

D-环丝氨酸 (DCS) 是一种部分 NMDA 受体激动剂，似乎是焦虑症暴露疗法的一种有前途的增强剂。它已在恐惧消退的动物模型中成功进行了测试，其中 DCS 增强了消退学习。DCS增强暴露疗法在临床研究中的应用结果仍然不明确，需要更深入地了解DCS的潜在机制及其对人类消退学习和恐惧回归（ROF）的确切影响。在本研究中，我们在 24 小时延迟回忆测试中研究了 DCS 增强消退学习对 ROF 的行为、心理生理和神经指标的影响。37 名参与者进入了随机、安慰剂对照、双盲、为期 3 天的恐惧调节和延迟消退功能磁共振成像设计。在消退训练前一小时，参与者口服 50 毫克 DCS 或安慰剂。行为唤醒评级显示安慰剂组在灭绝回忆过程中存在普遍的 ROF，但 DCS 组则不然。此外，与安慰剂相比，接受 DCS 的参与者在左后海马和杏仁核中从消退学习到消退回忆的差异 BOLD 反应减弱，这是由于安慰剂中海马募集增加以及 DCS 受试者中杏仁核反应呈趋势下降。我们发现 DCS 降低了唤醒等级的 ROF 和促进防御反应的神经结构，支持 NMDA 受体在消退记忆巩固中的作用，并鼓励进一步的转化研究。