Behavioral Biology Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA.
Psychopharmacology (Berl). 2020 Oct;237(10):2943-2958. doi: 10.1007/s00213-020-05582-0. Epub 2020 Jun 25.
Evaluation of pharmacotherapies for acute stress disorder (ASD) or post-traumatic stress disorder (PTSD) is challenging due to robust heterogeneity of trauma histories and limited efficacy of any single candidate to reduce all stress-induced effects. Pursuing novel mechanisms, such as the nociceptin/orphanin FQ (NOP) system, may be a viable path for therapeutic development and of interest as it is involved in regulation of relevant behaviors and recently implicated in PTSD and ASD.
First, we evaluated NOP receptor antagonism on general behavioral performance and again following a three-species predator exposure model (Experiment 1). Then, we evaluated effects of NOP antagonism on fear memory expression (Experiment 2).
Adult, male rats underwent daily administration of NOP antagonists (J-113397 or SB-612,111; 0-20 mg/kg, i.p.) and testing in acoustic startle, elevated plus maze, tail-flick, and open field tests. Effects of acute NOP antagonism on behavioral performance following predator exposure were then assessed. Separately, rats underwent fear conditioning and were later administered SB-612,111 (0-3 mg/kg, i.p.) prior to fear memory expression tests.
J-113397 and SB-612,111 did not significantly alter most general behavioral performance measures alone, suggesting minimal off-target behavioral effects of NOP antagonism. J-113397 and SB-612,111 restored performance in measures of exploratory behavior (basic movements on the elevated plus maze and total distance in the open field) following predator exposure. Additionally, SB-612,111 significantly reduced freezing behavior relative to control groups across repeated fear memory expression tests, suggesting NOP antagonism may be useful in dampening fear responses. Other measures of general behavioral performance were not significantly altered following predator exposure.
NOP antagonists may be useful as pharmacotherapeutics for dampening fear responses to trauma reminders, and the present results provide supporting evidence for the implication of the NOP system in the neuropathophysiology of dysregulations in fear learning and memory processes observed in trauma- and stress-related disorders.
由于创伤史的强异质性和任何单一候选药物减轻所有应激诱导效应的疗效有限，评估急性应激障碍（ASD）或创伤后应激障碍（PTSD）的药物治疗效果具有挑战性。探索新的机制，如孤啡肽/N 端前体（NOP）系统，可能是一种可行的治疗开发途径，并且因为它参与了相关行为的调节，并且最近与 PTSD 和 ASD 有关，所以很有研究意义。
首先，我们评估了 NOP 受体拮抗剂对一般行为表现的影响，然后在三种物种捕食者暴露模型后再次评估（实验 1）。然后，我们评估了 NOP 拮抗作用对恐惧记忆表达的影响（实验 2）。
成年雄性大鼠接受 NOP 拮抗剂（J-113397 或 SB-612,111；0-20mg/kg，ip）的每日给药，并在听觉惊跳、高架十字迷宫、尾部闪烁和旷场试验中进行测试。然后评估急性 NOP 拮抗作用对捕食者暴露后行为表现的影响。另外，大鼠进行恐惧条件反射，然后在恐惧记忆表达测试前给予 SB-612,111（0-3mg/kg，ip）。
J-113397 和 SB-612,111 单独使用时并未显著改变大多数一般行为表现测量值，表明 NOP 拮抗作用的脱靶行为影响最小。J-113397 和 SB-612,111 恢复了捕食者暴露后在高架十字迷宫上的基本运动和旷场中的总距离等探索行为测量值的表现。此外，与对照组相比，SB-612,111 在重复的恐惧记忆表达测试中显著减少了冻结行为，这表明 NOP 拮抗剂可能有助于抑制恐惧反应。其他一般行为表现测量值在捕食者暴露后并未显著改变。
NOP 拮抗剂可能作为药物治疗用于抑制对创伤提示的恐惧反应，并且本研究结果为 NOP 系统在创伤和应激相关障碍中观察到的恐惧学习和记忆过程失调的神经病理生理学中的作用提供了支持证据。
