Effect of paroxetine on enhanced contextual fear induced by single prolonged stress in rats
Effect of paroxetine on enhanced contextual fear induced by single prolonged stress in rats
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DOI：
10.1007/s00213-006-0545-6
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发表时间：
2006-12-01
影响因子：
3.4
通讯作者：
Yamawaki, Shigeto
中科院分区：
文献类型：
--
作者：
Takahashi, Terumichi;Morinobu, Shigeru;Yamawaki, Shigeto
基本原理 单一长期应激 (SPS) 是创伤后应激障碍 (PTSD) 的动物模型，可以重现增强的下丘脑 - 垂体 - 肾上腺负反馈。 目的 我们研究了 SPS 是否可以对与创伤无关的实验室应激源产生增强的心理生理反应，以及帕罗西汀 (PRX) 是否可以减轻接受 SPS 的大鼠增强的焦虑和恐惧反应。此外，在有和没有SPS的大鼠中检查PRX对疼痛敏感性的影响。方法对大鼠进行SPS（束缚2小时，强迫游泳20分钟，乙醚麻醉），然后保持不受干扰14天。之后，评估情境恐惧反应。足部电击调节后 24 小时，在重新暴露于电击环境 3 分钟期间测量冻结行为。通过退缩跳跃测试评估疼痛敏感性。将 PRX（0.01、0.03 或 0.1 mg/mL）溶解在饮用水中长期口服给药。 结果 与未接受 SPS 的大鼠相比，接受 SPS 的大鼠表现出情境冻结显着增加。长期施用浓度为 0.03 和 0.1 mg/mL 的 PRX（产生的血清浓度与临床相关浓度相似）会导致增强的情境冻结的显着抑制。以产生临床相关血清浓度的剂量急性施用 PRX 不会影响增强的冻结。结论我们的结果表明，SPS 可以重现与 PTSD 患者中观察到的类似的行为改变，并且这种升高的恐惧反应可以通过以产生临床相关血清浓度的剂量长期施用 PRX 来缓解。
Rationale Single prolonged stress (SPS) is an animal model of posttraumatic stress disorder (PTSD) that can reproduce enhanced hypothalamo-pituitary-adrenal negative feedback.Objectives We examined whether SPS can produce an enhanced psychophysiological reactivity to laboratory stressors unrelated to trauma and whether paroxetine (PRX) can alleviate the enhanced anxiety and fear response in rats subjected to SPS. Furthermore, the effect of PRX on pain sensitivity was examined in rats with and without SPS.Methods Rats were subjected to SPS (restraint for 2 h, forced swim for 20 min, and ether anesthesia) and then kept undisturbed for 14 days. After that, contextual fear response was assessed. Twenty-four hours after foot shock conditioning, freezing behavior was measured during reexposure to the shock environment for 3 min. Pain sensitivity was assessed by the flinch-jump test. PRX (0.01, 0.03, or 0.1 mg/mL) was chronically administered orally in drinking water.Results Rats subjected to SPS showed a significant increase in contextual freezing compared to rats without SPS. Chronic administration of PRX at concentrations of 0.03 and 0.1 mg/mL (which produced serum concentrations similar to those that are clinically relevant) caused significant suppression of the enhanced contextual freezing. Acute administration of PRX at a dose producing clinically relevant serum concentrations did not affect the enhanced freezing.Conclusions Our results suggest that SPS can reproduce behavioral alteration similar to that observed in patients with PTSD, and this elevated fear response can be alleviated by the chronic administration of PRX at doses producing clinically relevant serum concentrations.