Department of Clinical Psychology, University of Amsterdam, Amsterdam, The Netherlands.
Neuropsychopharmacology. 2012 Apr;37(5):1204-15. doi: 10.1038/npp.2011.307. Epub 2011 Dec 14.
The noradrenergic system plays a critical role in the 'consolidation' of emotional memory. If we are to target 'reconsolidation' in patients with anxiety disorders, the noradrenergic strengthening of fear memory should not impair the disruption of reconsolidation. In Experiment I, we addressed this issue using a differential fear conditioning procedure allowing selective reactivation of one of two fear associations. First, we strengthened fear memory by administering an α(2)-adrenergic receptor antagonist (ie, yohimbine HCl; double-blind placebo-controlled study) 30 min before acquisition (time for peak value yohimbine HCl <1 h). Next, the reconsolidation of one of the fear associations was manipulated by administering a β-adrenergic receptor antagonist (ie, propranolol HCl) 90 min before its selective reactivation (time for peak value propranolol HCl <2 h). In Experiment II, we administered propranolol HCl after reactivation of the memory to rule out a possible effect of the pharmacological manipulation on the memory retrieval itself. The excessive release of noradrenaline during memory formation not only delayed the process of extinction 48 h later, but also triggered broader fear generalization. Yet, the β-adrenergic receptor blocker during reconsolidation selectively 'neutralized' the fear-arousing aspects of the noradrenergic-strengthened memory and undermined the generalization of fear. We observed a similar reduction in fear responding when propranolol HCl was administered after reactivation of the memory. The present findings demonstrate the involvement of noradrenergic modulation in the formation as well as generalization of human fear memory. Given that the noradrenergic strengthening of fear memory impaired extinction learning but not the disruption of reconsolidation, our findings may have implications for the treatment of anxiety disorders.
去甲肾上腺素能系统在情绪记忆的“巩固”中起着关键作用。如果我们要针对焦虑障碍患者的“再巩固”，那么去甲肾上腺素能增强恐惧记忆不应损害再巩固的中断。在实验 I 中，我们使用差异恐惧条件作用程序来解决这个问题，该程序允许选择性地重新激活两个恐惧联想中的一个。首先，我们通过在获得之前 30 分钟（达到盐酸育亨宾的峰值时间<1 小时）给予α(2)-肾上腺素能受体拮抗剂（即盐酸育亨宾；双盲安慰剂对照研究）来增强恐惧记忆。接下来，通过在选择性重新激活之前 90 分钟给予β-肾上腺素能受体拮抗剂（即盐酸普萘洛尔）来操纵一个恐惧联想的再巩固（达到盐酸普萘洛尔的峰值时间<2 小时）。在实验 II 中，我们在记忆重新激活后给予盐酸普萘洛尔，以排除药物处理对记忆检索本身的可能影响。记忆形成过程中去甲肾上腺素的过度释放不仅延迟了 48 小时后消退的过程，还引发了更广泛的恐惧泛化。然而，再巩固期间的β-肾上腺素能受体阻滞剂选择性地“中和”了去甲肾上腺素增强记忆的唤起恐惧的方面，并破坏了恐惧的泛化。当在记忆重新激活后给予盐酸普萘洛尔时，我们观察到恐惧反应的类似减少。这些发现表明去甲肾上腺素能调制参与了人类恐惧记忆的形成和泛化。鉴于恐惧记忆的去甲肾上腺素能增强会损害消退学习但不会破坏再巩固，我们的发现可能对焦虑障碍的治疗具有意义。
