Biomedical Primate Research Centre (BPRC), Animal Science Department, Lange Kleiweg 161, 2288 GJ Rijswijk, the Netherlands.
Biomedical Primate Research Centre (BPRC), Animal Science Department, Lange Kleiweg 161, 2288 GJ Rijswijk, the Netherlands.
Eur Neuropsychopharmacol. 2021 Sep;50:1-11. doi: 10.1016/j.euroneuro.2021.04.004. Epub 2021 Apr 26.
Emotionally arousing experiences are retained very well as seen in posttraumatic stress disorder (PTSD). Various lines of evidence indicate that reactivation of these memories renders them labile which offers a potential time-window for intervention. We tested in non-human primates whether ketamine, administered during fear memory reactivation, affected passive (inhibitory) avoidance learning. For the consolidation of contextual emotional memory, the unescapable foot-shock paradigm in a passive avoidance task with two compartments (dark vs illuminated) was used. After entering the dark compartment, marmoset monkeys received four random foot-shocks (1 mA, 4 s) within 15-min. This stressful exposure increased the saliva cortisol and heart rate and impaired REM-sleep (p<0.05). One week later the monkeys were re-exposed to the stressful situation for the reconsolidation of the fearful experience. During the re-exposure the monkeys were treated with ketamine (0.5 mg/kg) or saline. In week 3, the monkeys were placed in the experimental setting to test their memory for the fearful experience. In contrast to the vehicle-treated monkeys, who avoided the dark compartment, the ketamine-treated monkeys entered the dark compartment that was previously associated with the fearful experience (p<0.05). Post-mortem analysis of the hippocampus showed that ketamine-treated animals exhibited less doublecortin positive neurons and BrdU-labeled cells in the dentate gyrus. This study reveals that a single low dose of ketamine, administered upon fear retrieval in monkeys, reduce contextual fear memory and attenuate neurogenesis in the hippocampus. These are important findings for considering ketamine as a potential candidate to target traumatic memories in PTSD.
情绪诱发的体验在创伤后应激障碍（PTSD）中被很好地保留下来。各种证据表明，这些记忆的重新激活使它们变得不稳定，这为干预提供了一个潜在的时间窗口。我们在非人类灵长类动物中测试了氯胺酮在恐惧记忆再激活期间的作用，是否会影响被动（抑制）回避学习。为了巩固情境情绪记忆，使用带有两个隔间（黑暗与照明）的被动回避任务中的不可逃避的足部电击范式。进入黑暗隔间后，狨猴在 15 分钟内接受了四次随机足部电击（1 mA，4 s）。这种压力暴露增加了唾液皮质醇和心率，并损害了 REM 睡眠（p<0.05）。一周后，猴子再次暴露于应激环境中，以重新巩固恐惧体验。在再暴露期间，猴子接受氯胺酮（0.5 mg/kg）或生理盐水治疗。在第 3 周，猴子被置于实验环境中，以测试它们对恐惧体验的记忆。与接受载体治疗的猴子相比，那些避免进入黑暗隔间的猴子进入了以前与恐惧体验相关的黑暗隔间（p<0.05）。海马体的死后分析表明，接受氯胺酮治疗的动物在齿状回中表现出较少的双皮质素阳性神经元和 BrdU 标记细胞。这项研究表明，在猴子中恐惧检索时给予单次低剂量氯胺酮可减少情境恐惧记忆，并减弱海马体中的神经发生。这些发现对于考虑氯胺酮作为 PTSD 中创伤性记忆的潜在治疗靶点具有重要意义。
