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

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(CB1)激动剂作为“认知增强剂”在创伤后应激中增加对消退学习的回忆 精神障碍(PTSD)。创伤后应激障碍的一线心理治疗是长期暴露(PE)，这涉及到反复 暴露在与恐惧相关的线索中会产生恐惧的“消退”。PE总体上是有效的，但许多患者 随着时间的推移，不完全灭绝或未能维持与灭绝学习相关的改进。召回灭绝事件 学习依赖于边缘-额叶大脑网络(海马体[HPC]、腹内侧额前皮质 [vmPFC])和创伤后应激障碍患者表现出这些区域的活动减少和消退回忆能力差。附属设备 解决vmPFC-HPC功能障碍和挽救灭绝回忆缺陷的干预措施可能会增强 PE治疗创伤后应激障碍的疗效观察令人信服的证据表明，在实验之前，急性口服剂量的THC 健康志愿者的恐惧消退程序通过增加激活促进消亡学习的回忆 以及vmPFC和HPC的功能连接性。作为灭绝回忆缺陷和vmPFC-HPC功能障碍 已经在创伤后应激障碍中观察到，研究结果表明大麻素系统是一个有希望的目标，以改善 体育学习对创伤后应激障碍治疗的有效性和持久性。因此，我们将检验THC的假设 将显著提高创伤后应激障碍患者对消退学习的回忆能力，并降低症状严重程度 这些效应将通过增加vmPFC和/或HPC的激活来介导。在R61阶段， PTSD患者将被随机分为三种情况之一(低5毫克THC；高10毫克THC；安慰剂[PBO])。 我们将把标准的巴甫洛夫恐惧消退模式与功能磁共振成像(FMRI)和皮肤电导结合起来 录音(SCR)，比较THC和PBO在灭绝学习之前的效果，测试回忆 灭绝学习后24小时和1周。如果THC(与PBO相比)显著增加灭绝 在创伤后应激障碍中召回并增加vmPFC和/或HPC的激活，R33阶段将测试THC对 降低创伤后应激障碍症状的严重程度，增加PE后的维持治疗。在R33阶段，创伤后应激障碍 患者将被随机分配到THC(从R61期确定的剂量)或PBO条件。THC或PBO 将在每次暴露前2小时在标准的人工PE治疗方案中进行。我们 将在THC后的每次PE就诊时评估治疗成功(PTSD症状严重程度降低)，并在3点再次评估 治疗后几个月探讨远期PE联合THC的疗效。与R61阶段一样，我们将使用 巴甫洛夫恐惧消退范式用于测量消退过程中恐惧消退回路中大脑的激活 回想治疗前后的测试，以确定THC是否增加了该回路的激活。团结在一起， R61和R33阶段将对创伤后应激障碍的THC效应提供最直接的转换和关键测试。发现 从这项研究中可以刺激大麻素的新的药理调节剂的开发 系统，以最大限度地发挥暴露治疗创伤后应激障碍的疗效。

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.