Effects of THC on Retention of Memory for Fear Extinction Learning in PTSD

该R61/R33的长期目标是使用Δ9 -四氢大麻酚（THC），一种1型大麻素 受体（CB 1）激动剂，作为一种“认知增强剂”，以增加记忆的灭绝学习创伤后应激 PTSD（PTSD）。PTSD的一线心理治疗是延长暴露（PE），这涉及重复的 暴露在与恐惧相关的线索中，产生恐惧的“灭绝”。PE通常有效，但许多患者 不完全灭绝或无法维持灭绝学习相关的改善。灭绝回忆 学习依赖于边缘额叶脑网络（海马[HPC]，腹内侧前额叶皮层 [vmPFC]）和PTSD患者在这些区域表现出活动减少和消退记忆差。附属物 解决vmPFC-HPC功能障碍和挽救灭绝回忆缺陷的干预措施可以增强 PE治疗PTSD的疗效令人信服的证据表明，急性口服剂量的四氢大麻酚，在实验之前， 健康志愿者的恐惧消退程序，通过增加激活促进消退学习的回忆 以及vmPFC和HPC的功能连接。由于消退回忆缺陷和vmPFC-HPC功能障碍 已经在PTSD中观察到，研究结果表明大麻素系统是一个有希望的目标，以改善 在治疗PTSD中，PE期间学习的有效性和持久性。因此，我们将测试THC 将显著增强PTSD患者对消退学习的回忆， 并且这些作用将通过增加vmPFC和/或HPC的活化来介导。在R61阶段， PTSD患者将被随机分配到三种条件之一（低5 mg THC;高10 mg THC;安慰剂[PBO]）。 我们将耦合一个标准的巴甫洛夫恐惧消退范式与功能性磁共振成像（fMRI）和皮肤电导 记录（SCR），以比较THC与PBO在消退学习之前的效果，测试回忆 消退学习后24小时和1周的消退学习。如果THC（相对于PBO）显著增加消光 回忆并增加PTSD中的vmPFC和/或HPC激活，R33阶段将测试THC的功效， 降低PTSD症状的严重程度，并增加PE后的维持治疗。在R33阶段，PTSD 患者将被随机分配到THC（从R61阶段确定的剂量）或PBO条件。THC或PBO 按照标准手动PE治疗方案，在每次暴露前2小时给药。我们 将在THC后的每次PE访视时评估治疗成功（减少PTSD症状严重程度），并在3 治疗后3个月，以探索长期PE与THC的联合作用。与R61阶段一样，我们将使用 巴甫洛夫恐惧消退范式测量灭绝期间恐惧消退回路中的大脑激活 治疗前和治疗后的回忆测试，以确定THC是否会增加该回路的激活。统称 R61和R33阶段将提供THC在PTSD中作用的最直接和关键的测试。结果 从这项研究中可以刺激大麻素的新药理学调节剂的开发 系统，以最大限度地提高创伤后应激障碍暴露疗法的疗效。

The long-term objective of this R61/R33 is to employ Δ9 -tetrahydrocannibinol (THC) a type 1 cannabinoid receptor (CB1) agonist, as a “cognitive enhancer” to increase recall of extinction learning in posttraumatic stress disorder (PTSD). First-line psychotherapy for PTSD is Prolonged Exposure (PE), which involves repeated exposure to fear-linked cues to produce “extinction” of fear. PE is generally effective, but many patients have incomplete extinction or fail to sustain extinction learning-related improvement over time. Recall of extinction learning depends upon limbic-frontal brain networks (hippocampus [HPC], ventromedial prefrontal cortex [vmPFC]) and PTSD patients show decreased activity in these regions and poor extinction recall. Adjunct interventions that address vmPFC-HPC dysfunction and rescue extinction recall deficits could enhance the efficacy of PE for PTSD. Compelling evidence suggests that an acute oral dose of THC, prior to experimental fear extinction procedures in healthy volunteers, facilitates recall of extinction learning via increased activation and functional connectivity of the vmPFC and HPC. As extinction recall deficits and vmPFC-HPC dysfunction have been observed in PTSD, findings indicate the cannabinoid system is a promising target to improve the efficacy and durability of learning during PE in treating PTSD. Accordingly, we will test the hypotheses that THC will significantly enhance the recall of extinction learning in patients with PTSD and reduce symptom severity and that these effects will be mediated via increased activation of the vmPFC and/or HPC. In the R61 phase, PTSD patients will be randomized to one of three conditions (low 5mg THC; high 10mg THC; placebo [PBO]). We will couple a standard Pavlovian fear extinction paradigm with functional MRI (fMRI) and skin conductance recordings (SCR) to compare the effects of THC vs PBO administered prior to extinction learning, testing recall of extinction learning 24 hr and 1 week after extinction learning. If THC (vs. PBO) significantly increases extinction recall and increases vmPFC and/or HPC activation in PTSD, the R33 phase will test the efficacy of THC to reduce PTSD symptom severity, and increase maintenance of treatment following PE. In the R33 phase, PTSD patients will be randomly assigned to a THC (dose identified from R61 phase) or PBO condition. THC or PBO will be administered 2 hr prior to each exposure session in a standard manualized PE treatment protocol. We will assess treatment success (reduced PTSD symptom severity) at each PE visit following THC and again at 3 months after treatment to explore long-term PE effects coupled with THC. Like the R61 phase, we will use a Pavlovian fear extinction paradigm to measure brain activation in fear extinction circuitry during an extinction recall test pre- and post-treatment to determine whether THC increases activation in this circuitry. Together, the R61 and R33 phases will provide the most directly translational and critical test of THC effects in PTSD. Findings from this investigation could stimulate development of novel pharmacological modulators of the cannabinoid system to maximize the efficacy of exposure therapy for PTSD.