Ritov G, Richter-Levin G
The Institute for the Study of Affective Neuroscience, University of Haifa, Haifa, Israel.
Sagol Department of Neurobiology, University of Haifa, Haifa, Israel.
Transl Psychiatry. 2017 Jan 10;7(1):e1000. doi: 10.1038/tp.2016.277.
In basic research, the etiology of fear-related pathologies, such as post-traumatic stress disorder (PTSD), is conceptualized using fear-conditioning protocols that pair environmental stimuli (that is, a conditioned stimulus-CS) with an aversive, unconditioned stimulus (US) to elicit an assessable conditioned fear response. Although pathophysiological models agree that regulatory dysfunctions in this associative process may instigate fear-related pathology, current opinions differ in regard to the nature of these dysfunctions. Primarily derived from studies in rodents, the prevailing perspective proposes that pathological fear-reactions develop from intensified and overly consolidated CS-US associations. Alternatively, models derived from studies in humans suggest that tempospatial inaccuracies in representations of associative fear might precipitate pathology by engendering failure to differentiate present experiences and past memories of threat. To test this concept in rodents, we administered rats with cognition enhancing doses of Methylphenidate before or after fear conditioning and measured long-term alterations in their conditioned fear behaviors and PTSD-like reactions. The administration of Methylphenidate before fear-memory formation indeed reduced anxious-like responses during fear-memory retrieval one month later. An individual profiling analysis revealed that Methylphenidate onset had opposing effects on the risk for PTSD-like classification. The modulation of initial learning and formation of associative fear normalized the risk for developing PTSD-like reaction. In contrast, when the effects of Methylphenidate were exerted only over later consolidation this risk increased markedly. When examined under current psychiatric and neuropharmacologic literature, these results reveal a possible strategy of using low-dose Methylphenidate for the prevention of PTSD in high risk populations.
在基础研究中，恐惧相关病症（如创伤后应激障碍，PTSD）的病因是通过恐惧条件化实验来概念化的，在这些实验中，将环境刺激（即条件刺激，CS）与厌恶的非条件刺激（US）配对，以引发可评估的条件性恐惧反应。尽管病理生理模型一致认为，这种关联过程中的调节功能障碍可能会引发与恐惧相关的病症，但目前对于这些功能障碍的本质存在不同观点。主要源于对啮齿动物的研究，主流观点认为病理性恐惧反应是由强化和过度巩固的CS-US关联发展而来。另外，源于对人类研究的模型表明，关联性恐惧表征中的时空不准确可能会导致无法区分当前经历和过去的威胁记忆，从而引发病症。为了在啮齿动物中验证这一概念，我们在恐惧条件化之前或之后给大鼠施用认知增强剂量的哌醋甲酯，并测量它们条件性恐惧行为和PTSD样反应的长期变化。在恐惧记忆形成之前施用哌醋甲酯确实减少了一个月后恐惧记忆检索期间的焦虑样反应。个体概况分析显示，哌醋甲酯的给药时机对PTSD样分类的风险有相反的影响。对关联恐惧的初始学习和形成进行调节可使发生PTSD样反应的风险正常化。相比之下，当哌醋甲酯的作用仅在后期巩固阶段发挥时，这种风险会显著增加。根据当前的精神病学和神经药理学文献进行研究时，这些结果揭示了一种使用低剂量哌醋甲酯预防高危人群患PTSD的可能策略。
