Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric Hospital, University of Zurich, Lenggstrasse 31, 8008, Zurich, Switzerland.
Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford, FMRIB Building, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
Psychopharmacology (Berl). 2024 May;241(5):1065-1077. doi: 10.1007/s00213-024-06540-w. Epub 2024 Feb 9.
Previous work identified an attenuating effect of the matrix metalloproteinase (MMP) inhibitor doxycycline on fear memory consolidation. This may present a new mechanistic approach for the prevention of trauma-related disorders. However, so far, this has only been unambiguously demonstrated in a cued delay fear conditioning paradigm, in which a simple geometric cue predicted a temporally overlapping aversive outcome. This form of learning is mainly amygdala dependent. Psychological trauma often involves the encoding of contextual cues, which putatively necessitates partly different neural circuits including the hippocampus. The role of MMP signalling in the underlying neural pathways in humans is unknown.
Here, we investigated the effect of doxycycline on configural fear conditioning in a double-blind placebo-controlled randomised trial with 100 (50 females) healthy human participants.
Our results show that participants successfully learned and retained, after 1 week, the context-shock association in both groups. We find no group difference in fear memory retention in either of our pre-registered outcome measures, startle eye-blink responses and pupil dilation. Contrary to expectations, we identified elevated fear-potentiated startle in the doxycycline group early in the recall test, compared to the placebo group.
Our results suggest that doxycycline does not substantially attenuate contextual fear memory. This might limit its potential for clinical application.
先前的研究发现基质金属蛋白酶（MMP）抑制剂强力霉素对恐惧记忆巩固具有抑制作用。这可能为预防与创伤相关的疾病提供新的机制方法。然而，到目前为止，这仅在提示性延迟恐惧条件反射范式中得到明确证实，在该范式中，简单的几何提示预测了时间上重叠的厌恶结果。这种形式的学习主要依赖于杏仁核。心理创伤通常涉及情境线索的编码，这可能需要部分不同的神经回路，包括海马体。MMP 信号在人类潜在的神经通路中的作用尚不清楚。
在这里，我们在一项有 100 名（50 名女性）健康人类参与者参与的双盲安慰剂对照随机试验中，研究了强力霉素对组态恐惧条件反射的影响。
我们的结果表明，参与者在两组中都成功地学习并在 1 周后保留了上下文-冲击关联。我们在我们预先注册的两种结果测量方法中都没有发现组间在恐惧记忆保留方面的差异，即眨眼反射和瞳孔扩张的惊跳反应。与预期相反，与安慰剂组相比，我们在回忆测试的早期发现强力霉素组的惊跳反应增强，这表明恐惧增强。
我们的结果表明，强力霉素并没有显著减弱情境恐惧记忆。这可能限制了它在临床应用中的潜力。
