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标志，如创伤后应激障碍（PTSD）、恐慌症和恐惧症。恐惧的消除发生在暴露疗法中；然而，这是暂时的，恐惧经常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。增强与消失记忆保留有关的神经和神经化学底物将是解决这一挑战的关键。动物研究表明，在杏仁核、海马体和腹内侧前额叶皮层（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，可以增强恐惧消退及其保留。具体来说，CB1受体激动剂，如？9-四氢大麻酚（THC）可以通过阻止大鼠消失恐惧的恢复来促进灭绝记忆。然而，这种现象尚未在人类中进行调查，但应该进行调查。本概念验证项目旨在评估四氢大麻酚在消退训练后24小时和1周内对消退学习回忆和底层神经回路激活（HPC, vmPFC）的影响，并确定消退学习后24小时回忆测试中观察到的四氢大麻酚对vmPFC-HPC激活的增强是否介导了消退保留（1周后）的维持。在随机、双盲、安慰剂对照、受试者之间的设计中，我们将在fMRI中结合标准的巴甫洛夫恐惧消退范式和同时进行的皮肤电导记录，在健康成年志愿者（n=80）中，在消退学习之前口服合成四氢大麻酚的急性药理挑战，并在24小时和1周后测试消退保留和维持消退学习，以及恐惧更新。这项概念验证研究提供了最具翻译性、影响力、信息量和关键的测试，也是开发大麻素调节剂作为暴露疗法的辅助策略的第一步，以增强消退保留并防止创伤后应激障碍和其他焦虑症患者恐惧记忆的恢复。相关性：焦虑障碍的暴露疗法依赖于消退学习，对许多患者仅是暂时或部分有效。本研究将测试大麻素激动剂是否可以增强灭绝保留及其神经基质，并转化动物研究的新发现，大麻素系统是优化暴露治疗期间进行的学习以增强和保持其成功的有希望的目标。

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.