Cannabinoid Control of Fear Extinction Neural Circuits In Humans

描述（由申请人提供）：不能抑制不适当的恐惧反应是焦虑症的标志，例如创伤后应激障碍（PTSD）、恐慌症和恐怖症。在暴露疗法期间，恐惧会消失;然而，这是暂时的，恐惧往往会随着时间的推移而重新出现（自发恢复），破坏了治疗效果的维持。增强与记忆消退保持有关的神经和神经化学物质对解决这一挑战至关重要。动物研究表明，杏仁核、海马体和腹内侧前额叶皮层（分别为AMYG、HPC、vmPFC）内大麻素系统的激活，对恐惧表达和消退学习至关重要的大脑结构，增强了恐惧消退及其保留。具体而言，CB 1受体激动剂，如？9-四氢大麻酚（THC）可以通过阻止大鼠消除恐惧的恢复来促进消失回忆。然而，这种现象尚未在人类中进行过研究，但应该进行研究。这个概念验证项目的具体目的是评估THC在消退训练后24小时和1周测试时对消退学习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）的维持是否由消退学习后24小时回忆测试期间观察到的THC增强vmPFC-HPC激活介导。在一项随机、双盲、安慰剂对照、受试者间设计中，我们将在健康成年志愿者（n=80）中，在消退学习之前，将fMRI中的标准巴甫洛夫恐惧消退范式和同步皮肤电导记录与口服合成THC的急性药理学挑战相结合，并在24小时和1周后测试消退保持和消退学习的维持，以及恐惧的更新。这项概念验证研究提供了最具转化性，影响力，信息量和关键性的测试，并迈出了大麻素调节剂开发的第一步，作为一种基于免疫疗法的预防策略，以增强消退保留并防止PTSD和其他焦虑症患者恐惧记忆的恢复。相关性：焦虑症的暴露疗法依赖于消退学习，对许多患者仅暂时或部分有效。这项研究将测试大麻素激动剂是否可以增强消光保留及其神经底物，并将动物研究的新发现转化为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，以增强和保持其成功。

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.