Separating the agony from ecstasy: R(-)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice.
Separating the agony from ecstasy: R(-)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice.
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DOI：
10.1016/j.neuropharm.2017.10.003
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发表时间：
2018-01
影响因子：
4.7
通讯作者：
Howell LL
中科院分区：
文献类型：
--
作者：
Curry DW;Young MB;Tran AN;Daoud GE;Howell LL
S，R(+/−)-3，4-亚甲基二氧基甲基苯丙胺(SR-MDMA)，是一种具有亲社会和潜在治疗作用的苯丙胺衍生物。正在进行的临床试验正在研究它作为一种治疗创伤后应激障碍(PTSD)和其他疾病的方法。然而，其潜在的不良反应，如高热和神经毒性可能限制其临床生存能力。我们研究了SR-MDMA的两个对映体之一，R-MDMA，将保留亲社会和治疗作用，但不良反应较少的假设。使用雄性瑞士Webster和C57BL/6小鼠，通过社会互动测试来衡量R-MDMA的亲社会效应，并使用与创伤后应激障碍相关的巴甫洛夫恐惧条件反射和消退范式来评估治疗样效应。给药后追踪动物的活动和体温，并在死后评估神经毒性。R-MDMA显著增加了小鼠的社会互动，促进了条件性冰冻的消退。然而，与外消旋MDMA不同的是，它不会增加运动活性，不会产生神经毒性的迹象，也不会提高体温。R-MDMA和外消旋MDMA之间的一个关键的药理差异是R-MDMA作为多巴胺释放剂的效力要低得多。用选择性的多巴胺D1拮抗剂预防SR-MDMA诱导的体温升高，表明不同的多巴胺信号可能解释了观察到的治疗之间的一些差异。总之，这些结果表明，SR-MDMA的亲社会和治疗作用可能与刺激性、生热性和潜在的神经毒性作用分开。这些发现在多大程度上适用于人类还需要进一步的研究，但这些数据表明，R-MDMA可能是治疗创伤后应激障碍和其他疾病的更可行的治疗选择，SR-MDMA目前正在研究中。
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 postmortem. 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 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.
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影响因子：
3.7
作者：
Hysek CM;Simmler LD;Nicola VG;Vischer N;Donzelli M;Krähenbühl S;Grouzmann E;Huwyler J;Hoener MC;Liechti ME
通讯作者：
Liechti ME
DOI：
10.4161/23328940.2014.955433
发表时间：
2014-10
期刊：
Temperature (Austin, Tex.)
影响因子：
--
作者：
Liechti ME
通讯作者：
Liechti ME
影响因子：
2.8
作者：
Halpern, Pinchas;Moskovich, Jenny;Peleg, Kobi
通讯作者：
Peleg, Kobi
影响因子：
168.9
作者：
HENRY, JA;JEFFREYS, KJ;DAWLING, S
通讯作者：
DAWLING, S
影响因子：
2.3
作者：
Granado, Noelia;Escobedo, Isabel;Moratalla, Rosario
通讯作者：
Moratalla, Rosario