Departments of Psychology and Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Biol Psychiatry. 2013 Feb 15;73(4):345-52. doi: 10.1016/j.biopsych.2012.08.006. Epub 2012 Sep 12.
Fears that are maladaptive or inappropriate can be reduced through extinction training. However, extinction is highly context-sensitive, resulting in the renewal of fear after shifts in context and limiting the clinical efficacy of extinction training. Lesion and inactivation studies have shown that the contextualization of extinction depends on the hippocampus. Parallel studies have found that intrahippocampal scopolamine (Scop) blocks contextual fear conditioning. Importantly, this effect was replicated with a noninvasive technique in which a low dose of Scop was administered systemically. We aimed to transfer the effects of this noninvasive approach to block the contextualization of fear extinction.
Rats were tone fear conditioned and extinguished under various systemic doses of Scop or the saline vehicle. They were subsequently tested (off drug) for tone fear in a context that was the same (control subjects) or shifted (renewal group) with respect to the extinction context.
The lowest dose of Scop produced a significant attenuation of fear renewal when renewal was tested either in the original training context or a novel context. The drug also slowed the rate of long-term extinction memory formation, which was readily overcome by extending extinction training. Scopolamine only gave this effect when it was administered during but not after extinction training. Higher doses of Scop severely disrupted extinction learning.
We discovered that disrupting contextual processing during extinction with the cholinergic antagonist Scop blocked subsequent fear renewal. Low doses of Scop might be a clinically promising adjunct to exposure therapy by making extinction more relapse-resistant.
通过消除训练可以减少适应不良或不适当的恐惧。然而，消除是高度上下文敏感的，导致在上下文转移后恐惧的重现，并限制了消除训练的临床疗效。损伤和失活研究表明，消除的语境化取决于海马体。平行研究发现，海马内东莨菪碱（Scop）阻断情境性恐惧条件作用。重要的是，这种效应可以通过一种非侵入性技术复制，其中系统给予低剂量的 Scop。我们旨在将这种非侵入性方法的效果转移到阻断恐惧消除的语境化。
大鼠在各种系统剂量的 Scop 或盐水载体下进行音调恐惧条件作用和消除。然后，他们在与消退背景相同（对照）或转移（更新组）的背景下（停药后）进行音调恐惧测试。
当在原始训练背景或新背景中测试更新时，最低剂量的 Scop 显著减弱了恐惧的重现。该药物还减缓了长期消退记忆形成的速度，通过延长消退训练很容易克服。Scop 只有在消退训练期间而不是之后给予时才会产生这种效果。更高剂量的 Scop 严重破坏了消退学习。
我们发现，在消退过程中用胆碱能拮抗剂 Scop 破坏上下文处理会阻止随后的恐惧重现。低剂量的 Scop 可能是暴露疗法的一种有前途的临床辅助手段，使消退更能抵抗复发。
