Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave., St. John's, Newfoundland A1B3X9, Canada.
Neurobiol Learn Mem. 2011 May;95(4):453-60. doi: 10.1016/j.nlm.2011.02.006. Epub 2011 Feb 17.
The pharmacology of traumatic memory extinction has not been fully characterized despite its potential as a therapeutic target for established, acquired anxiety disorders, including post-traumatic stress disorder (PTSD). Here we examine the role of endogenous glucocorticoids in traumatic memory extinction.
Male C57BL/6J mice were injected with corticosterone (10 mg/kg, i.p.) or metyrapone (50 mg/kg, s.c.) during re-activation of a contextual fear memory, and compared to vehicle groups (N=10-12 per group). To ensure that metyrapone was blocking corticosterone synthesis, we measured corticosterone levels following re-activation of a fear memory in metyrapone- and vehicle-treated animals.
Corticosterone administration following extinction trials caused a long-lasting inhibition of the original fear memory trace. In contrast, blockade of corticosteroid synthesis with metyrapone prior to extinction trials enhanced retrieval and prevented extinction of context-dependent fear responses in mice. Further behavioral analysis suggested that the metyrapone enhancement of retrieval and prevention of extinction were not due to non-specific alterations in locomotor or anxiety-like behavior. In addition, the inhibition of extinction by metyrapone was rescued by exogenous administration of corticosterone following extinction trials. Finally, we confirmed that the rise in corticosterone during re-activation of a contextual fear memory was blocked by metyrapone.
We demonstrate that extinction of a classical contextual fear memory is dependent on endogenous glucocorticoid synthesis during re-activation of a fear memory. Our data suggest that decreased glucocorticoids during fear memory re-activation may contribute to the inability to extinguish a fear memory, thus contributing to one of the core symptoms of PTSD.
尽管创伤性记忆遗忘在治疗创伤后应激障碍（PTSD）等已建立的获得性焦虑障碍方面具有潜在作用，但它的药理学特性尚未得到充分描述。在这里，我们研究了内源性糖皮质激素在创伤性记忆遗忘中的作用。
雄性 C57BL/6J 小鼠在重新激活情境性恐惧记忆时接受皮质酮（10mg/kg，腹腔注射）或美替拉酮（50mg/kg，皮下注射）治疗，并与载体组（每组 10-12 只）进行比较。为确保美替拉酮阻断皮质酮合成，我们在美替拉酮和载体处理动物重新激活恐惧记忆后测量了皮质酮水平。
在遗忘试验后给予皮质酮会导致原始恐惧记忆痕迹的持久抑制。相比之下，在遗忘试验之前用美替拉酮阻断皮质类固醇合成增强了检索并防止了小鼠对情境相关恐惧反应的遗忘。进一步的行为分析表明，美替拉酮增强检索和防止遗忘不是由于运动或焦虑样行为的非特异性改变。此外，在遗忘试验后给予外源性皮质酮可以挽救美替拉酮对遗忘的抑制作用。最后，我们证实了美替拉酮对遗忘的抑制作用可以通过在重新激活情境性恐惧记忆时阻断皮质酮的合成来恢复。
我们证明了经典情境性恐惧记忆的遗忘依赖于恐惧记忆重新激活期间的内源性糖皮质激素合成。我们的数据表明，恐惧记忆重新激活期间皮质酮的减少可能导致无法遗忘恐惧记忆，从而导致 PTSD 的核心症状之一。
