Single dose of L-dopa makes extinction memories context-independent and prevents the return of fear
Single dose of L-dopa makes extinction memories context-independent and prevents the return of fear
复制标题
DOI：
10.1073/pnas.1303061110
复制
发表时间：
2013-06-25
影响因子：
11.1
通讯作者：
Kalisch, Raffael
中科院分区：
文献类型：
--
作者：
Haaker, Jan;Gaburro, Stefano;Kalisch, Raffael
创伤事件会导致对创伤提示的持续过度恐惧反应，即使在成功治疗后也可能复发。灭绝，行为疗法的实验室模拟，不会消除条件性恐惧记忆，但会产生竞争性的、恐惧抑制性的“灭绝记忆”，然而，这些记忆与灭绝发生的背景有关。因此，如果在灭绝（治疗）背景之外遇到熄灭的恐惧刺激，通常会观察到恐惧对灭绝记忆表达的主导作用，从而返回恐惧。我们发现，灭绝后给予多巴胺前体左旋多巴使灭绝记忆与上下文无关，从而大大减少了小鼠和人类恐惧的回归。在这两个物种中，恐惧的减少伴随着杏仁核的减少和腹内侧前额叶皮层激活的增强。在人类中，腹内侧前额叶皮质的活动是通过在灭绝后巩固阶段增强该区域与多巴胺能中脑的静息态功能耦合来预测的。我们的数据表明，多巴胺依赖性增强消退记忆巩固是改善焦虑治疗的一个有希望的途径。
Traumatic events can engender persistent excessive fear responses to trauma reminders that may return even after successful treatment. Extinction, the laboratory analog of behavior therapy, does not erase conditioned fear memories but generates competing, fear-inhibitory "extinction memories" that, however, are tied to the context in which extinction occurred. Accordingly, a dominance of fear over extinction memory expression-and, thus, return of fear-is often observed if extinguished fear stimuli are encountered outside the extinction (therapy) context. We show that postextinction administration of the dopamine precursor L-dopa makes extinction memories context-independent, thus strongly reducing the return of fear in both mice and humans. Reduced fear is accompanied by decreased amygdala and enhanced ventromedial prefrontal cortex activation in both species. In humans, ventromedial prefrontal cortex activity is predicted by enhanced resting-state functional coupling of the area with the dopaminergic midbrain during the postextinction consolidation phase. Our data suggest that dopamine-dependent boosting of extinction memory consolidation is a promising avenue to improving anxiety therapy.