Department of Psychology, BS101, Charles E. Schmidt College of Science, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431-0991, USA.
Neuropharmacology. 2013 Jan;64(1):403-13. doi: 10.1016/j.neuropharm.2012.06.007. Epub 2012 Jun 18.
Excessive fear is a hallmark of several emotional and mental disorders such as phobias and panic disorders. Considerable attention is focused on defining the neurobiological mechanisms of the extinction of conditioned fear memory in an effort to identify mechanisms that may hold clinical significance for remediating aberrant fear memory. Serotonin modulates the acquisition and retention of conditioned emotional memory, and the serotonin 2A receptor (5HT2AR) may be one of the postsynaptic targets mediating such effects. Here we tested the hypothesis that the 5HT2AR regulates the consolidation and extinction of fear memory in male C57BL/6J mice. The influence of 5HT2ARs on memory consolidation was further confirmed with a novel object recognition task. With a trace fear conditioning paradigm, administration of the 5HT2AR agonist TCB-2 (1.0 mg/kg, i.p.) before the extinction test facilitated the acquisition of extinction of fear memory as compared to vehicle treatment. In contrast, administration of the 5HT2AR antagonist MDL 11,939 (0.5 mg/kg, i.p.) delayed the acquisition of extinction of fear memory. Further, the post-conditioning administration of TCB-2 enhanced contextual and cued fear memory, possibly by facilitating the consolidation of fear memory. Administration of TCB-2 also facilitated the acquisition of extinction of fear memory in delay fear conditioned mice. Stimulation or blockade of 5HT2ARs did not affect the encoding or retrieval of conditioned fear memory. Finally, administration of TCB-2 right after training in an object recognition task enhanced the consolidation of object memory. These results suggest that stimulation of 5HT2ARs facilitates the consolidation and extinction of trace and delay cued fear memory and the consolidation of object memory. Blocking the 5HT2AR impairs the acquisition of fear memory extinction. The results support the view that serotonergic activation of the 5HT2AR provides an important modulatory influence on circuits engaged during extinction learning. Taken together these results suggest that the 5HT2AR may be a potential therapeutic target for enhancing hippocampal and amygdala-dependent memory. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
过度恐惧是恐惧症和惊恐障碍等多种情绪和精神障碍的标志。人们高度关注定义条件性恐惧记忆消除的神经生物学机制，以期确定对纠正异常恐惧记忆具有临床意义的机制。血清素调节条件性情绪记忆的获得和保持，而血清素 2A 受体（5HT2AR）可能是介导这种作用的突触后靶点之一。在这里，我们检验了 5HT2AR 调节雄性 C57BL/6J 小鼠恐惧记忆巩固和消除的假设。使用新物体识别任务进一步证实了 5HT2AR 对记忆巩固的影响。使用痕迹恐惧条件反射范式，与载体处理相比，在消退测试前给予 5HT2AR 激动剂 TCB-2（1.0mg/kg，ip）可促进恐惧记忆消退的获得。相反，给予 5HT2AR 拮抗剂 MDL 11,939（0.5mg/kg，ip）则延迟了恐惧记忆消退的获得。此外，TCB-2 的条件后给药增强了上下文和线索恐惧记忆，可能通过促进恐惧记忆的巩固来实现。TCB-2 的给药也促进了延迟恐惧条件的小鼠恐惧记忆消退的获得。5HT2AR 的刺激或阻断均不影响条件性恐惧记忆的编码或检索。最后，在物体识别任务的训练后立即给予 TCB-2 可增强物体记忆的巩固。这些结果表明，5HT2AR 的刺激促进了痕迹和延迟线索恐惧记忆的巩固和消退，以及物体记忆的巩固。阻断 5HT2AR 会损害恐惧记忆消退的获得。这些结果支持了这样一种观点，即 5HT2AR 的血清素激活对消退学习过程中涉及的回路提供了重要的调节影响。综上所述，这些结果表明 5HT2AR 可能是增强海马和杏仁核依赖性记忆的潜在治疗靶点。本文是题为“认知增强剂”的特刊的一部分。
