Neural circuitry and synaptic physiology underlying MDMA's prosocial effect

创伤后应激障碍(PTSD)对平民和退伍军人的福祉都造成了沉重的损失。 迫切需要标准治疗的替代方案。典型的创伤后应激障碍治疗，例如长期使用 5-羟色胺选择性再摄取抑制剂(SSRI)与心理治疗相结合，确实有助于相当数量的 患者，但它未能治疗大多数创伤后应激障碍患者。最近，难治性创伤后应激障碍患者 通过一种令人惊讶的治疗，MDMA协助，他们的症状实现了戏剧性和持久的缓解 心理治疗。消遣药物MDMA，也被称为“摇头丸”，曾被用作治疗焦虑的辅助药物。 和创伤后应激障碍，在1985年合法化之前。最近批准的临床试验表明，MDMA辅助 心理治疗对创伤后应激障碍安全有效。MDMA增强信任感、情感开放性和 同理心，帮助创伤后应激障碍患者克服治疗障碍，如极端愤怒、情绪麻木 和压倒性的焦虑。这个项目旨在定义生物学和神经生理学，它们创造了 MDMA的亲社会效应。通过定义MDMA亲社会的治疗效果的机制，我们可以开始 创造新的治疗方法，利用相同的潜在生物过程。提高社会生活质量 互动对社交能力受损的许多障碍都有影响，从自闭症到严重的抑郁症。 值得注意的是，在初步临床试验中，患者在经历了一次 在心理治疗的背景下使用MDMA剂量。此外，MDMA的治疗开始可以用 几分钟和几小时，而不是SSRI典型的几周和几个月。MDMA的迅速兴起和持久 治疗效果表明，它是通过治疗手段促进行为恢复的有力催化剂。 突触可塑性；行为的急剧变化反映了神经回路、神经元和 突触。这个定义明确的时间窗口极大地简化了对潜在神经的搜索 其亲社会效应的机制。如果我们能在这个短片上测量MDMA最显著的治疗方面 时间尺度，我们可以设计实验，明确地测试其机制的要求，使用工具 非常适合急性测量和干预。 最近对小鼠的社会奖励和相互作用的研究表明，5-羟色胺和多巴胺的释放在 伏隔核(NAC)是大脑中集中参与奖赏和社会互动的区域。这个项目将 系统地评估这些元素在MDMA机制中的作用 药理学、脑区特异性药物注射、光遗传学和神经活动的成像 行为。最后，这项研究将对MDMA如何产生短期和长期的 NAC内突触的时程效应。

Post-traumatic stress disorder (PTSD) exacts a steep toll on the well being of civilians and veterans alike. Alternatives to standard treatment are urgently needed. Typical PTSD therapy, e.g. long-term treatment with a serotonin-selective reuptake inhibitor (SSRI) coupled with psychotherapy, does help a significant number of patients, but it fails to treat the majority of PTSD sufferers. Recently, patients with treatment-resistant PTSD have achieved dramatic and durable remission of their symptoms with a surprising treatment, MDMA-assisted psychotherapy. The recreational drug MDMA, also known as “ecstasy”, had been used as an aid to treat anxiety and PTSD prior to its illegalization in 1985. Recently approved clinical trials demonstrate that MDMA-assisted psychotherapy is safe and effective for PTSD. MDMA enhances feelings of trust, emotional openness and empathy, helping PTSD patients overcome obstacles to therapy, such as extreme anger, emotional numbing and overwhelming anxiety. This project aims to define the biology and the neurophysiology that create the prosocial effect of MDMA. By defining the mechanism for MDMA's prosocial, therapeutic effect we can begin creating new treatments that harness the same underlying biological processes. Improving the quality of social interaction has implications for many disorders where sociability is impaired, from autism to major depression. Remarkably, patients in preliminary clinical trials have experienced years-long remission of PTSD after a single dose of MDMA in the context of psychotherapy. Further, MDMA's therapeutic onset can be measured in minutes and hours rather than the weeks and months typical of SSRIs. MDMA's rapid onset and lasting therapeutic effect suggest that it is a powerful catalyst for behavioral recovery by means of therapeutic synaptic plasticity; an acute change in behavior reflects plasticity at the level of neural circuits, neurons, and synapses. This well-defined time window dramatically simplifies the search for an underlying neural mechanism of its prosocial effect. If we can measure MDMA's most salient therapeutic aspects on this short time scale, we can design experiments that explicitly test the requirements for its mechanism, using tools ideally suited to acute measurement and intervention. Recent studies of social reward and interaction in mice implicate serotonin and dopamine release in the nucleus accumbens (NAc), a brain area centrally involved in reward and social interaction. This project will systematically evaluate the role of each of these elements in MDMA's mechanism using behavioral pharmacology, brain region-specific drug injection, optogenetics, and imaging of neurons' activity during behavior. Finally this study will carry out a detailed examination of how MDMA produces both short- and long- term effects on synapses in the NAc.