Cannabinoid Control of Fear Extinction Neural Circuits In Humans

描述(由申请人提供)：无法抑制不适当的恐惧反应是焦虑症的特征，如创伤后应激障碍(PTSD)、恐慌和恐惧症。恐惧的消退发生在暴露治疗期间；然而，这是暂时的，恐惧往往随着时间的推移而重新出现(自发恢复)，破坏了治疗成果的维持。增强神经和神经化学底物参与消亡记忆的保持将是解决这一挑战的关键。动物研究表明，杏仁核、海马体和前额叶腹内侧皮质(分别为AMYG、HPC和vmPFC)中大麻素系统的激活，对恐惧表达和消退学习至关重要的大脑结构，可以增强恐惧的消退和保持。具体地说，CB1受体激动剂，如？9-四氢大麻酚(THC)，可以通过阻止大鼠消除的恐惧的恢复来促进消退回忆。然而，这种现象还没有，但应该在人类身上进行研究。该概念验证项目旨在评估THC在消退训练后24小时和1周测试时对消退学习的回忆和潜在神经回路激活(HPC，vmPFC)的影响，并确定消退保持(1周后)的维持是否通过THC在消退学习后24小时的回忆测试中观察到的vmPFC-HPC激活所介导。在一项随机、双盲、安慰剂对照的受试者间设计中，我们将结合fMRI中的标准巴甫洛夫恐惧消退范例和同步皮肤电导记录，在健康成年志愿者(n=80)消退学习之前使用口服合成THC进行急性药理学挑战，并测试24小时和一周后消退学习的消退保持和保持，以及恐惧的更新。这项概念验证研究提供了最具翻译性、有效性、信息性和关键性的测试和开发大麻素调节剂的第一步，作为基于暴露的治疗的辅助策略，以增强PTSD和其他焦虑症患者的消退保持和防止恐惧记忆的回归。相关性：暴露疗法治疗焦虑症依赖于消退学习，对许多患者来说只是暂时或部分有效。这项研究将测试大麻素激动剂是否可以增强灭绝保持及其神经底物，并转化动物研究的新发现，即大麻素系统是优化暴露治疗期间进行的学习的有希望的目标，以加强和维持其成功。

DESCRIPTION (provided by applicant): The inability to suppress inappropriate fear responses is the hallmark of anxiety disorders, such as post- traumatic stress disorder (PTSD), panic, and phobia disorders. Extinction of fear occurs during exposure therapy; however, this is temporary and fear often re-emerges with the passage of time (spontaneous recovery), undermining the maintenance of therapeutic gains. Enhancing the neural and neurochemical substrates involved in retention of extinction memory will be critical to solving this challenge. Animal studies have shown that activation of the cannabinoid system within the amgydala, hippocampus, and ventromedial prefrontal cortex (AMYG, HPC, vmPFC, respectively), brain structures critical to fear expression and extinction learning, enhances fear extinction and its retention. Specifically, CB1 receptor agonists, such as ?9- tetrahydrocannibinol (THC), can facilitate extinction recall by preventing recovery of extinguished fear in rats. However, this phenomenon has not been, but should be, investigated in humans. This proof-of-concept project specifically aims to assess the effects of THC on the recall of extinction learning and underlying neural circuit activation (HPC, vmPFC) when tested 24 hours and 1 week after extinction training, and to determine if the maintenance of extinction retention (1 week later) is mediated by the enhancement of vmPFC-HPC activation by THC observed during a recall test 24 hours after extinction learning. In a randomized, double-blind, placebo-controlled, between-subjects design, we will couple a standard Pavlovian fear extinction paradigm in fMRI and simultaneous skin conductance recordings with an acute pharmacological challenge with oral, synthetic THC prior to extinction learning in healthy adult volunteers (n=80) and test extinction retention and maintenance of extinction learning at 24 hours and 1 week later, as well as fear renewal. This proof-of-concept study provides the most translational, impactful, informative, and critical test and first step towards the development of cannabinoid modulators as an adjunctive strategy to exposure-based therapies to augment extinction retention and prevent the return of fear memories in patients with PTSD and other anxiety disorders. Relevance: Exposure therapy for anxiety disorders relies on extinction learning and is only temporarily or partially effective for many patients. This study will test if a cannabinoid agonist can enhance extinction retention and its neural substrates, and translate emerging findings from animal studies that the cannabinoid system is a promising target for optimizing the learning that goes on during exposure treatment in order to enhance and maintain its success.