PMC

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.

Effect of different doses of MDMA on striatal dopamine and dopamine metabolite concentrations 7 days later. Mice were administered MDMA (25 mg kg⁻¹ i.p.) or saline three times at 3 h intervals. Results shown as mean±s.e. mean (n=5 – 6). (a) Striatal dopamine concentrations. MDMA treatment resulted in a significant reduction in dopamine levels in both MDMA (×3) and MDMA (×2) groups, compared to saline-treated control mice (***P<0.001) and compared to the MDMA (×1) group (ΔΔΔP<0.001), while there was no significant difference between MDMA (×3) and MDMA (×2) treatment groups. (b) Dopamine loss measured 1 week following administration of 1, 2 or 3 doses of MDMA, calculated as a % of control values. (c) Striatal DOPAC concentrations. MDMA treatment resulted in a significant reduction in DOPAC levels in both MDMA (×3) and MDMA (×2) groups, compared to saline-treated control mice (**P<0.01) and compared to the MDMA (×1) group (ΔP<0.05, (ΔΔP<0.01). There was no significant difference between MDMA (×3) and MDMA (×2) treatment groups. (d) Striatal HVA concentrations. MDMA treatment resulted in a significant reduction in HVA levels in the MDMA (×2) treatment group, compared to saline-treated control mice (*P<0.05), while there was no significant difference between MDMA (×3) and MDMA (×2) treatment groups.

MDMA Self-Administration Sessions: Lever Responses and MDMA Intake. Mean daily lever responses and total MDMA intake (mg/kg) (+/− SEM) during (A) Acquisition (Session Days 1–10) and (B) Maintenance (Session Days 11–20). During Acquisition, MDMA dose was 1.0 mg/kg/inj and 0.5 mg/kg/inj during Maintenance sessions. Groups included: MDMA Room Temperature (n = 8), MDMA High Temperature (n = 8), Control Room Temperature (n =8), and Control High Temperature (n =8). Ambient temperature did not influence lever responding in either the MDMA or Control groups across all sessions. (A) All groups were trained to lever press for food reinforcement prior to MDMA sessions. The high number of responses for the first 2 sessions in both Control groups is a characteristic food extinction response pattern. Lever responses of the Control groups were significantly greater than MDMA groups during Acquisition (++ = both Control groups significantly greater than both MDMA groups @ p <0.01). (B) Lever responses in the MDMA groups were significantly greater than Controls (*, ** = both MDMA groups significantly greater than both Control groups @ p <0.05 and 0.01, respectively). Bar Insert: Total MDMA Intake (both MDMA groups combined) was significantly greater during Maintenance (B) compared to the Acquisition (A) interval.

Locomotor sensitization after MDMA two-injection protocol in WT and 5-HT_2B^−/− mice (A–D): MDMA (10 mg/kg i.p.) increases locomotor activity after the first injection (1^st) in WT mice but not in 5-HT_2B ^−/− mice A) or RS127445-treated WT mice B). The stimulant effect of a challenge dose of MDMA (10 mg/kg) 7 days later (2^nd) was significantly enhanced compared to the first injection in WT mice, while it had no effect in 5-HT_2B ^−/− mice A) or RS127445 pre-treated WT mice B). To evaluate the role of 5-HT_2B receptors in the development of locomotor sensitization, WT mice were treated with RS127445 30 min before the first injection of MDMA. The increased responsiveness to the challenge injection of MDMA in absence of RS127445 was totally abolished C). MDMA (30 mg/kg i.p.) induces locomotor activity after the first injection in WT and 5-HT_2B ^−/− mice compared to saline injection D). The stimulant effect of a challenge dose of MDMA (30 mg/kg) was significantly enhanced compared to the first injection in both WT and 5-HT_2B ^−/− mice D). Data (means±SEM, n = 8−14 per group) were analyzed by two-way ANOVA with genotype (A–D) or RS127445 pre-treatment (B–C) and MDMA treatment as main factors. A significant interaction was observed for the locomotor activity in figure A) F (2,66) = 12.86 p<0.01, and B) F (2,54) = 11.49 p<0.01, as well as a main effect of genotype F (2, 66) = 15.68, p<0.001 (A) or RS127445 pre-treatment F (2, 54) = 10.24, p<0.05 (B) and of MDMA treatment F (1,66) = 9.26, p<0.001 (A), and F (1,54) = 17.04, p<0.001 (B). No significant interaction was observed for the locomotor activity in figure C) F (2,66) = 3.57, ns, whereas a main effect of RS127445 pre-treatment at the 1^st MDMA injection, F (2,66) = 28.56, p<0.001, and of MDMA treatment F (1,66) = 6.64, p<0.01 were detected. Neither a significant interaction, F (2,50) = 0.25, ns, nor a main effect of genotype F (1,50) = 0.9, ns, was observed for the locomotor activity in figure D), whereas a main effect of MDMA treatment, F (2,50) = 82.72, p<0.001, was detected. Bonferroni tests were used for post-hoc comparisons. The null hypothesis was rejected at the p<0.05 level; *p<0.05; **p<0.01; ***p<0.001 compared to saline-treated mice. °p<0.05; °°°p<0.001 compared to MDMA 1^st injection. Locomotor sensitization after repeated MDMA injection in WT and 5-HT_2B^−/− mice (E): MDMA (10 mg/kg i.p.) increases locomotor activity after the first injection (day 1; d1) in WT mice but not in 5-HT_2B ^−/− mice compare to saline injection. Repeated MDMA injection during the following days (Day 2 to 5, d2–d5) increases locomotor activity only in WT mice. The stimulant effect of a challenge dose of MDMA (10 mg/kg) 5 days later (day 10; d10) was significantly enhanced compared to the first injection in WT mice, while it had no effect in 5-HT_2B ^−/− mice. Data (means±SEM, n = 8 per group) were analyzed by two-way ANOVA with genotype and MDMA treatment as main factors. Bonferroni tests were used for post-hoc comparisons. The null hypothesis was rejected at the p<0.05 level; **p<0.01; ***p<0.001 compared to saline-treated mice. °°°p<0.001 compared to MDMA day 1 injection.