Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
Neurosci Lett. 2011 Jan 25;488(3):242-6. doi: 10.1016/j.neulet.2010.11.038. Epub 2010 Nov 19.
Extinction of conditioned fear response is thought to be a biological process underlying exposure therapy for anxiety disorders. We have previously reported that an AMPA receptor potentiator, 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluorophenoxyacetamide (PEPA), facilitates extinction of fear memory formed through contextual fear conditioning in mice that had never been exposed to experimental stress. On the other hand, recent findings suggest that the fear extinction is impaired in stressed rats or mice. The purpose of the present study was to examine whether PEPA facilitates impaired extinction of fear in stressed mice. For this purpose, mice were applied stress (a 2h restraint, a 20min forced swim, and ether inhalation), and contextual fear conditioning was carried out 7 days later. After 1-3 days of conditioning, mice were re-exposed to the context for 6min, and behavioral freezing response was measured. The time mice spent frozen decreased following every extinction session, and the decrease was remarkably slower in the stressed mice than in control non-stressed mice. PEPA (3, 10, 30mg/kg body weight) or vehicle was intraperitoneally administered into stressed mice once before the first extinction session. The significant decrease of the freezing response in the extinction sessions was only seen in the 30mg/kg PEPA-administered stressed mice, compared with vehicle-administered stressed mice. A similar extent of decrease in the freezing response in the extinction sessions was observed in the PEPA-administered (30mg/kg) and d-cycloserine-administered (30mg/kg) mice. These results suggest that PEPA facilitates extinction of contextual fear in stressed mice.
条件性恐惧反应的消除被认为是焦虑症暴露疗法的生物学基础。我们之前曾报道过，AMPA 受体增强剂 4-[2-(苯磺酰胺基)乙硫基]-2,6-二氟苯氧乙酰胺（PEPA）促进了从未接触过实验应激的小鼠通过情境恐惧条件反射形成的恐惧记忆的消除。另一方面，最近的研究结果表明，应激会损害大鼠或小鼠的恐惧消除。本研究的目的是检验 PEPA 是否促进应激小鼠的恐惧消除受损。为此，对小鼠施加应激（2 小时束缚、20 分钟强迫游泳和乙醚吸入），7 天后进行情境恐惧条件反射。在 1-3 天的条件反射后，将小鼠重新暴露于环境中 6 分钟，并测量行为性冻结反应。每次消除训练后，小鼠的冻结时间减少，而应激小鼠的减少速度明显慢于非应激对照小鼠。在第一次消除训练前，将 PEPA（3、10、30mg/kg 体重）或载体通过腹腔注射到应激小鼠体内。只有在 30mg/kg PEPA 处理的应激小鼠中，才观察到在消除训练中冻结反应的显著下降，而在载体处理的应激小鼠中则没有。在消除训练中，PEPA（30mg/kg）和 d-环丝氨酸（30mg/kg）处理的小鼠的冻结反应也有类似程度的下降。这些结果表明，PEPA 促进了应激小鼠的情境恐惧消除。
