MDMA treatment paired with a trauma-cue promotes adaptive stress responses in a translational model of PTSD in rats

In a rat model of posttraumatic stress disorder (PTSD), a single dose of MDMA (5 mg/kg) paired with a trauma reminder cue reduced anxiety-like behaviors and normalized stress-induced changes in brain structure (dendritic complexity in the dentate gyrus and basolateral amygdala) two weeks later. The treatment was effective only when MDMA was combined with memory reactivation; without the trauma cue, no behavioral improvement occurred. Blocking the HPA axis or serotonin receptors (with RU486, ketanserin, or pindolol) prevented these effects, suggesting MDMA's action involves both stress hormone and serotonin systems. The findings indicate MDMA may help update traumatic memories through reconsolidation processes.

Study at a glance

Abstract

AbstractMDMA (3,4-methylenedioxymethamphetamine), a synthetic ring-substituted amphetamine, combined with psychotherapy has demonstrated efficacy for the treatment of chronic posttraumatic stress disorder (PTSD) patients. This controlled prospective study aimed to assess the bio-behavioral underpinnings of MDMA in a translational model of PTSD. Rats exposed to predator-scent stress (PSS) were subjected to a trauma-cue at day 7 shortly after single-dose MDMA injection (5 mg/kg). The elevated plus maze and acoustic startle response tests were assessed on day 14 and served for classification into behavioral response groups. Freezing response to a further trauma-reminder was assessed on Day 15. The morphological characteristics of the dentate gyrus (DG) and basolateral amygdala (BLA) were subsequently examined. Hypothalamic–pituitary–adrenal axis and 5-hydroxytryptamine involvement were evaluated using: (1) corticosterone measurements at 2 h and 4 h after MDMA treatment, (2) Lewis strain rats with blunted HPA-response and (3) pharmacological receptor-blockade. MDMA treatment was effective in attenuating stress behavioral responses only when paired with memory reactivation by a trauma-cue. The effects of the treatment on behavior were associated with a commensurate normalization of the dendritic cytoarchitecture of DG and BLA neurons. Pretreatment with RU486, Ketanserin, or Pindolol prevented the above improvement in anxiety-like behavioral responses. MDMA treatment paired with memory reactivation reduced the prevalence rate of PTSD-phenotype 14 days later and normalized the cytoarchitecture changes induced by PSS (in dendritic complexities) compared to saline control. MDMA treatment paired with a trauma-cue may modify or update the original traumatic memory trace through reconsolidation processes. These anxiolytic-like effects seem to involve the HPA axis and 5-HT systems.