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. 2022 May 3;12(1):181.
doi: 10.1038/s41398-022-01952-8.

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

Shira Arluk  1 , Michael A Matar  2 , Lior Carmi  3 , Oded Arbel  4 , Joseph Zohar  3 , Doron Todder  2 , Hagit Cohen  5   6
Affiliations

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

Shira Arluk et al. Transl Psychiatry. .

Abstract

MDMA (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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. MDMA treatment 30 min before trauma-cue at 7 days after trauma, attenuates behavioral stress responses The top panel (1) depicts the experimental protocol.
Vertical arrows represent intraperitoneal MDMA (5 mg/kg) or saline injection. Rats were exposed for 10 min to predator-scent stress (PSS) or to sham-PSS on day 0. On day 7, rats received MDMA (sham-PSS + MDMA: n = 10; PSS-exposed + MDMA: n = 10) or saline (sham-PSS + saline: n = 11; PSS-exposed + saline: n = 10) and 30 min later were exposed to a trauma-cue for 10 min. During this time A LMA (distance moved; measured in cm); B Percent freezing response; C Representative patterns of locomotor activity (cumulated values) in all groups. Behavioral measurements (EPM and ASR) were performed on day 14 and freezing behavior on day 15. D Anxiety index, which integrates the measured EPM behavioral measures; E Startle amplitude in the ASR paradigm: F Percentage of startle habituation in the ASR paradigm. G Representative accumulated movement track during a trial. H Prevalence of extreme behavioral response (EBR) vs. partial behavioral response (PBR) and minimal behavioral response (MBR) rats (in percentages). Significant differences were found between groups in the prevalence rates of individuals displaying an extreme, minimal, and partial behavioral response (Pearson χ2 = 18.85, df = 10, p < 0.0045). Finally, effect of trauma-cue at day 15 on LMA I (distance moved; measured in cm); and J Percent freezing response. K Representative patterns of locomotor activity (cumulated values) in all groups. The experiments described below were performed with two different cohorts of animals; 20 rats were run in one experimental design (5 rats/each group), and 21 rats in another experimental design (5–6 rats/each group). Bars represent group means ± SEM and percentages.
Fig. 2
Fig. 2. MDMA treatment paired with a trauma-cue at 7 days after trauma, normalized morphological indicators.
The top panel (1) depicts the experimental protocol. Vertical arrows represent intraperitoneal MDMA (5 mg/kg) or saline injection. Rats were exposed for 10 min to predator-scent stress (PSS) or to sham-PSS on day 0. On day 7, rats received MDMA (sham-PSS + MDMA: n = 10; PSS-exposed + MDMA: n = 10) or saline (sham-PSS + saline: n = 11; PSS-exposed + saline: n = 10) and 30 min later were exposed to a trauma-cue for 10 min. On Day 16, rats were sacrificed and their brains collected for morphological staining. A Sholl analysis for intersections per 15-μm radial unit distance of dentate gyrus granule cells from the suprapyramidal blade. * Sham-PSS + MDMA ≠ PSS + MDMA, p < 0.05. #PSS + saline ≠ PSS + MDMA, p < 0.05. @PSS + saline ≠ PSS + MDMA, sham-PSS + saline, p < 0.05. B Sholl analysis for intersections per 15-μm radial unit distance of pyramidal neurons of the basolateral amygdala. ^PSS + saline ≠ sham-PSS + saline & sham-PSS + MDMA, p < 0.03. * PSS + saline ≠ sham-PSS + saline & sham-PSS + MDMA & PSS + MDMA, p < 0.03. @PSS + saline ≠ sham-PSS + saline & PSS + MDMA, p < 0.05. #PSS + saline ≠ sham-PSS + saline, p < 0.04. C Computer-generated reconstructions of dendritic trees from granule cells and pyramidal cells in all groups. (2) depicts the experimental protocol. Vertical arrows represent intraperitoneal MDMA (5 mg/kg) or saline injection. Corticosterone concentrations (pg/ml) measured at 120- and 240 min post MDMA treatment in sham-PSS treated with saline (Sham-PSS + saline, n = 10) or MDMA (Sham-PSS + MDMA, n = 10), PSS-exposed animals treated with saline (PSS + saline, n = 10), or PSS-exposed treated with MDMA (PSS-MDMA, n = 9). D corticosterone concentrations** (pg/ml) were measured. The experiments described below were performed with two different cohorts of animals; 20 rats were run in one experimental design, and 19 rats in another experimental design. Bars represent group means ± SEM.
Fig. 3
Fig. 3. MDMA treatment timely paired with trauma-cue attenuates behavioral stress responses (1) Top panel: experimental protocol.
Vertical arrows represent intraperitoneal MDMA (5 mg/kg) or saline injection. Rats were exposed for 10 min to predator-scent stress (PSS) on day 0. On day 7, rats received MDMA or saline and 30 min later were exposed for 10 min to a reminder (PSS + saline + Reminder: n = 9; PSS + MDMA + reminder (Paired): n = 8) or not (without reminder) (PSS + saline alone: n = 9; PSS + MDMA alone: n = 10). In addition, 2 groups of rats were exposed to PSS and six days thereafter, MDMA or saline were administered, one day before exposure to the situational reminder (PSS + saline + Reminder: n = 8; PSS + MDMA + Reminder (unpaired): n = 10). During this time A LMA (distance moved; measured in cm); B Percent freezing response [Two-way ANOVA: Treatment effect: (F(1,32) = 16.75, p < 0.0003)]; C Representative patterns of locomotor activity (cumulated values) in all groups. Behavioral measurements (EPM and ASR) were performed on day 14 and freezing behavior on day 15. D Anxiety index, which integrates the measured EPM behavioral measures; E Startle amplitude in the ASR paradigm; F Percentage of startle habituation in the ASR paradigm. G Representative accumulated movement track during a trial. H Prevalence of extreme behavioral response (EBR) vs. partial behavioral response (PBR) and minimal behavioral response (MBR) rats (in percentages). Significant differences were found between groups in the prevalence rates of individuals displaying an extreme, minimal, and partial behavioral response (Pearson χ2 = 17.62, df = 6, p < 0.0075). Finally, the effect of trauma-cue at day 15 on LMA (I) (distance moved; measured in cm; and J Percent freezing response. K Representative patterns of locomotor activity (cumulated values) in all groups. The experiments described below were performed with three different cohorts of animals; 19 rats were run in one experimental design, 17 rats in another experimental design and 18 rats in a third experimental design. Bars represent group means ± SEM and percentages.
Fig. 4
Fig. 4. In Lewis rats, MDMA treatment has no long-term behavioral effects (1) Top panel: experimental protocol.
Vertical arrows represent intraperitoneal MDMA (5 mg/kg) or saline injection. Lewis rats were exposed for 10 min to predator-scent stress (PSS) or to sham-PSS on day 0. On day 7, rats received MDMA (sham-PSS + MDMA: n = 6; PSS-exposed + MDMA: n = 6) or saline (sham-PSS + saline: n = 6; PSS-exposed + saline: n = 8) and 30 min later were exposed to a trauma-cue for 10 min. During this time A LMA (distance moved; measured in cm); B Percent freezing response; C Representative patterns of locomotor activity (cumulated values) in all groups. D Urine corticosterone concentrations (pg/ml) were measured. Behavioral measurements (EPM and ASR) were performed on day 14 and freezing behavior on day 15. E Anxiety index, which integrates the measured EPM behavioral measures; F Startle amplitude in the ASR paradigm; G Percentage of startle habituation in the ASR paradigm. H Representative accumulated movement track during a trial. I Prevalence of extreme behavioral response (EBR) vs. partial behavioral response (PBR) and minimal behavioral response (MBR) rats (in percentages). Finally, the effect of trauma-cue at day 15 on LMA J (distance moved; measured in cm); and K Percent freezing response; L Representative patterns of locomotor activity (cumulated values) in all groups. The experiments described below were performed with two different cohorts of animals; 13 rats were run in one experimental design, and 13 rats in another experimental design. Bars represent group means ± SEM and percentages.
Fig. 5
Fig. 5. The glucocorticoid receptor and the serotonin receptors 5-HT-1A and 5-HT-2A are necessary for the anxiolytic effects of MDMA: (1) Top panel: experimental protocol.
Rats were exposed for 10 min to predator-scent stress (PSS) on day 0. On day 7 rats were intraperitoneally injected with either saline, Ru486 (7.5 mg) (GR antagonist mifepristone), Ketanserin (5 mg/kg) (5-HT2A R antagonist), Pindolol (0.3 mg/kg) (5-HT1A R antagonist) or SB242084 (0.3 mg/kg) (5-HT2C R antagonist) and 30 min before MDMA (5 mg/kg|) or saline injection, administered 30 min before a brief memory reactivation session. There were 6 rats per group. During this time A LMA (distance moved; measured in cm); B Percent freezing response; C Representative patterns of locomotor activity (cumulated values) in all groups. D Urine corticosterone concentrations** (pg/ml). Behavioral measurements (EPM and ASR) were performed on day 14 and freezing behavior on day 15. E Anxiety index, which integrates the measured EPM behavioral measures; F Startle amplitude in the ASR paradigm; G Percentage of startle habituation in the ASR paradigm. H Representative accumulated movement track of the rats during a trial. Finally, the effect of trauma-cue at day 15 on LMA I (distance moved; measured in cm); and J Percent freezing response; K Representative patterns of locomotor activity (cumulated values) in all groups. The experiments described below were performed with two different cohorts of animals; 18 rats were run in one experimental design, and 18 rats in another experimental design. Bars represent group means ± SEM and percentages.
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