Girgenti Matthew J, Ghosal Sriparna, LoPresto Dora, Taylor Jane R, Duman Ronald S
Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA.
Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA.
Neurobiol Dis. 2017 Apr;100:1-8. doi: 10.1016/j.nbd.2016.12.026. Epub 2016 Dec 30.
Impaired fear extinction contributes to the persistence of post-traumatic stress disorder (PTSD), and can be utilized for the study of novel therapeutic agents. Glutamate plays an important role in the formation of traumatic memories, and in the pathophysiology and treatment of PTSD, highlighting several possible drug targets. Recent clinical studies demonstrate that infusion of ketamine, a glutamate NMDA receptor antagonist, rapidly and significantly reduces symptom severity in PTSD patients. In the present study, we examine the mechanisms underlying the actions of ketamine in a rodent model of fear conditioning, extinction, and renewal. Rats received ketamine or saline 24h after fear conditioning and were then subjected to extinction-training on each of the following three days. Ketamine administration enhanced extinction on the second day of training (i.e., reduced freezing behavior to cue) and produced a long-lasting reduction in freezing on exposure to cue plus context 8days later. Additionally, ketamine and extinction exposure increased levels of mTORC1 in the medial prefrontal cortex (mPFC), a region involved in the acquisition and retrieval of extinction, and infusion of the selective mTORC1 inhibitor rapamycin into the mPFC blocked the effects of ketamine on extinction. Ketamine plus extinction also increased cFos in the mPFC and administration of a glutamate-AMPA receptor antagonist blocked the effects of ketamine. These results support the hypothesis that ketamine produces long-lasting mTORC1/protein synthesis and activity dependent effects on neuronal circuits that enhance the expression of extinction and could represent a novel approach for the treatment of PTSD.
恐惧消退受损会导致创伤后应激障碍（PTSD）持续存在，可用于新型治疗药物的研究。谷氨酸在创伤性记忆的形成以及PTSD的病理生理学和治疗中发挥重要作用，这凸显了几个可能的药物靶点。近期临床研究表明，输注氯胺酮（一种谷氨酸N-甲基-D-天冬氨酸受体拮抗剂）可迅速且显著降低PTSD患者的症状严重程度。在本研究中，我们研究了氯胺酮在恐惧条件反射、消退和恢复的啮齿动物模型中的作用机制。大鼠在恐惧条件反射后24小时接受氯胺酮或生理盐水注射，然后在接下来的三天每天进行消退训练。氯胺酮给药增强了训练第二天的消退（即降低对线索的僵住行为），并在8天后暴露于线索加情境时使僵住行为产生持久减少。此外，氯胺酮和消退暴露增加了内侧前额叶皮质（mPFC）中mTORC1的水平，mPFC是一个参与消退获取和恢复的区域，向mPFC注射选择性mTORC1抑制剂雷帕霉素可阻断氯胺酮对消退的作用。氯胺酮加消退还增加了mPFC中的cFos，给予谷氨酸-AMPA受体拮抗剂可阻断氯胺酮的作用。这些结果支持了这样的假设，即氯胺酮对神经元回路产生持久的mTORC1/蛋白质合成和活性依赖性作用，增强消退的表达，可能代表一种治疗PTSD的新方法。
