Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Psychiatry and Behavioral Science, Emory University School of Medicine, Atlanta, GA 30322, USA.
Neuropharmacology. 2018 Jan;128:196-206. doi: 10.1016/j.neuropharm.2017.10.003. Epub 2017 Oct 6.
S,R(+/-)-3,4-methylenedioxymethamphetamine (SR-MDMA) is an amphetamine derivative with prosocial and putative therapeutic effects. Ongoing clinical trials are investigating it as a treatment for post-traumatic stress disorder (PTSD) and other conditions. However, its potential for adverse effects such as hyperthermia and neurotoxicity may limit its clinical viability. We investigated the hypothesis that one of the two enantiomers of SR-MDMA, R-MDMA, would retain the prosocial and therapeutic effects but with fewer adverse effects. Using male Swiss Webster and C57BL/6 mice, the prosocial effects of R-MDMA were measured using a social interaction test, and the therapeutic-like effects were assessed using a Pavlovian fear conditioning and extinction paradigm relevant to PTSD. Locomotor activity and body temperature were tracked after administration, and neurotoxicity was evaluated post-mortem. R-MDMA significantly increased murine social interaction and facilitated extinction of conditioned freezing. Yet, unlike racemic MDMA, it did not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature. A key pharmacological difference between R-MDMA and racemic MDMA is that R-MDMA has much lower potency as a dopamine releaser. Pretreatment with a selective dopamine D1 receptor antagonist prevented SR-MDMA-induced hyperthermia, suggesting that differential dopamine signaling may explain some of the observed differences between the treatments. Together, these results indicate that the prosocial and therapeutic effects of SR-MDMA may be separable from the stimulant, thermogenic, and potential neurotoxic effects. To what extent these findings translate to humans will require further investigation, but these data suggest that R-MDMA could be a more viable therapeutic option for the treatment of PTSD and other disorders for which SR-MDMA is currently being investigated.
S,R(+/-)-3,4-亚甲二氧基甲基苯丙胺（SR-MDMA）是一种苯丙胺衍生物，具有亲社会和潜在的治疗作用。目前正在进行临床试验，以研究其作为创伤后应激障碍（PTSD）和其他疾病的治疗方法。然而，其潜在的副作用，如体温升高和神经毒性，可能会限制其临床应用。我们研究了一种假设，即 SR-MDMA 的两个对映异构体之一，R-MDMA，可能会保留亲社会和治疗作用，但副作用较少。使用雄性瑞士 Webster 和 C57BL/6 小鼠，通过社交互动测试测量 R-MDMA 的亲社会作用，通过与 PTSD 相关的 Pavlovian 恐惧条件反射和消退范式评估其治疗样作用。给药后跟踪运动活动和体温，死后评估神经毒性。R-MDMA 显著增加了小鼠的社交互动，并促进了条件性冻结的消退。然而，与外消旋 MDMA 不同，它不会增加运动活动、产生神经毒性迹象或升高体温。R-MDMA 和外消旋 MDMA 的一个关键药理学差异是，R-MDMA 作为多巴胺释放剂的效力要低得多。预先用选择性多巴胺 D1 受体拮抗剂处理可防止 SR-MDMA 引起的体温升高，这表明多巴胺信号的差异可能解释了两种治疗方法之间观察到的一些差异。总之，这些结果表明，SR-MDMA 的亲社会和治疗作用可能与兴奋剂、致热和潜在神经毒性作用分离。这些发现在多大程度上适用于人类还需要进一步研究，但这些数据表明，R-MDMA 可能是治疗 PTSD 和其他目前正在研究的疾病的更可行的治疗选择。
