Research ArticlePSYCHIATRIC DISEASES

Distinct neural mechanisms for the prosocial and rewarding properties of MDMA

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Science Translational Medicine  11 Dec 2019:
Vol. 11, Issue 522, eaaw6435
DOI: 10.1126/scitranslmed.aaw6435
  • Fig. 1 MDMA enhances social preference in mice.

    (A) Three-chamber social interaction assay schematic with experimental timeline. (B) Time spent with “mouse cup” versus “empty cup” after increasing doses of MDMA (n = 9 to 13). SAL, saline; ns, not significant. (C) Time course of social preference during 30-min exploration after lowest effective dose of MDMA (7.5 mg/kg) compared to saline treatment (n = 14 to 16). Yellow box indicates the time of maximal MDMA effect. (D) Summary of sociability index in final 10 min. (E) MDMA’s prosocial effect as a function of mice receiving MDMA or saline injections (n = 12 to 20). (F) Locomotor activity after either saline, the lowest effective dose of MDMA in the three-chamber assay (7.5 mg/kg), or a higher dose of MDMA (15 mg/kg; n = 10 to 11). (G) Conditioned place preference (CPP) schematic using a single 1-hour pairing of context with MDMA. (H) Preference for MDMA-paired side, before and after conditioning (n = 10 to 11). CPP data is shown after low-dose (left) and higher-dose MDMA (right). Data shown are means ± SEM. Significance was determined for each comparison (statistical test): across groups (one-way ANOVA, unmatched) for (B), (E), and (F); across group time courses (two-way ANOVA, ordinary) for (C); between groups (unpaired t test) for (D); within group (paired t test) for (H); all planned post hoc between-group comparison (t test with Sidak correction for multiple comparisons). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001; ns, P > 0.05.

  • Fig. 2 MDMA’s interaction with SERT accounts for its prosocial, but not its rewarding, effects.

    (A) Sociability in mice pretreated (preTx) with saline or the SSRI, SCIT, before treatment (Tx) with MDMA or saline. Saline + MDMA group is compared to SCIT + saline and SCIT + MDMA groups (n = 6 to 9). (B) Schematic of SERT cKO mouse, which has exons 3 and 4 floxed. (C) Schematic of AAV containing Cre-eGFP injected into the DR of adult SERTwt/wt, SERTfl/wt, and SERTfl/fl mice. (D) Sample images of immunohistochemistry of Cre-eGFP–injected DR from a wild-type mouse and SERTfl/fl littermate; coronal brain section represents area enclosed by dashed box in (C). 5-HTergic cells visualized by tryptophan hydroxylase (TPH). (eGFP, green; anti-SERT, red; anti-TPH2, cyan; scale bars, 100 μm). (E) Sociability after MDMA (7.5 mg/kg) in Cre-eGFP–injected wild-type mice and in heterozygous and homozygous SERT cKO mice (n = 8 to 22). (F) CPP data after high-dose MDMA (15 mg/kg) in all three groups of mice from (E) (n = 11 to 22). Preference for MDMA-paired side is shown before and after conditioning. (G) Sociability in mice pretreated with saline or a selective DAT inhibitor, JHW-007 (10 mg/kg), before treatment with MDMA or saline. JHW + MDMA group is compared to saline + saline, and JHW + saline groups (n = 8 to 15). (H) Time course of sociability index after METH administration (2 mg/kg) versus saline (SAL; n = 9 to 10). (I) Locomotor sensitization after METH (2 mg/kg) is given on successive days (n = 8). (J) Preference for METH-paired side in a CPP assay (J; n = 12). Data shown are means ± SEM. Significance was determined for each comparison (statistical test): across groups (one-way ANOVA, unmatched) for (A) and (G); between groups (unpaired t test) for (E); within group (paired t test) for (F) and (J); across group time courses (two-way ANOVA, ordinary) for (H); within group time course (one-way ANOVA, repeated measures) for (I); all planned post hoc between-group comparison (t test with Sidak correction for multiple comparisons). *P < 0.05, **P < 0.01, and ****P < 0.0001; ns, P > 0.05.

  • Fig. 3 MDMA’s prosocial, but not its rewarding, effect requires interaction with SERT in NAc.

    (A) Left: Schematic of drug infusion into the NAc. Right: Sociability in mice pretreated with saline or SCIT infused into the NAc before intraperitoneal treatment with MDMA or saline. Saline-NAc + MDMA-intaperitoneal is compared to SCIT-NAc + saline-intraperitoneal and SCIT-NAc + MDMA intraperitoneal groups. n = 15 to 20. (B) Left: Schematic of drug infusion into the VTA. Right: Sociability in mice pretreated with saline or SCIT infused into the VTA before intraperitoneal treatment with MDMA or saline. Saline-VTA + MDMA-intraperitoneal is compared to SCIT-VTA + saline-intraperitoneal and SCIT-VTA + MDMA intraperitoneal groups. n = 13 to 18. (C) Left: Schematic as in (A). Right: Sociability in mice pretreated with saline or MDMA infused into the NAc before intraperitoneal treatment with MDMA or saline. Saline-NAc + saline-intraperitoneal is compared to saline-NAc + MDMA-intaperitoneal and MDMA-NAc + saline intraperitoneal groups (n = 11 to 13). (D) CPP data after MDMA (15 mg/kg) in mice pretreated with either saline, SCIT, or the D2R antagonist raclopride (RAC) infused into the NAc (n = 13 to 16). (E) Schematic of fiber photometry experiments. GCaMP6f was expressed in DR 5-HT neurons to allow imaging of their projections within the NAc during the three-chamber assay. (F and G) GCaMP6f fluorescence from SERT-expressing neurons terminals in the NAc after MDMA (7.5 mg/kg). (F) Sample trace. Arrow denotes intraperitoneal MDMA injection. (G) Summary graph of SD of ΔF/F during 5-min epoch after either saline (SAL) or MDMA (7.5 mg/kg), normalized to SD of ΔF/F during the 5 min before injection (n = 3). (H) Sample trace illustrating GCaMP6f transients from SERT+ terminals in the NAc during three-chamber exploration. (I) Spatial heat map example. The maximal ΔF/F occurring for each explored area of the three-chamber apparatus is shown for one 30-min session. Outlines of mouse cup (left) and empty cup (right) are drawn. (J) Summary graph of z-scored fluorescence as a function of distance from the mouse cup. (K) Summary graph of cumulative z-scored fluorescence for the area around the mouse cup versus empty cup (n = 5 mice). (L) Ratio of mouse cup to empty cup–related GcaMP6f fluorescence as function of the ratio of time spent in the same two areas. Data shown are means ± SEM. Significance was determined for each comparison (statistical test): across groups (one-way ANOVA, unmatched) for (A) to (C); within group (paired t test) for (D); between groups (unpaired t test) for (G) and (K); univariate correlation (linear regression) for (L); all planned post hoc between-group comparison (t test with Sidak correction for multiple comparisons). *P < 0.05, **P < 0.01, and ****P < 0.0001; ns, P > 0.05.

  • Fig. 4 MDMA’s prosocial effect requires 5-HT release and activation of 5-HT1b receptors in NAc.

    (A) Schematic for slice electrophysiology from coronal brain slices containing NAc. (B) Left: Summary time course graph showing the effect of a 10-min bath application of MDMA (10 μM) on EPSC amplitudes recorded from D1 and D2 MSNs. Right, sample EPSC traces taken from time points 1 and 2 as shown. (C) Summary graph shows EPSC amplitudes in D1 and D2 MSNs after MDMA application (n = 7 to 8 cells, 6 to 7 mice). (D) Sociability in mice pretreated with one of several dose regimens of the OxtR antagonist (OTRA), L-368,899, before treatment with MDMA or saline. OTRA + saline group is compared to groups receiving MDMA and pretreatment with the following: saline; OTRA (5 mg/kg once); HI (10 mg/kg once); or MULTI (5 mg/kg every 12 hours for 48 hours preceding MDMA; n = 8 to 12). (E) Sociability in mice pretreated with saline or OTRA infused into the NAc before intraperitoneal treatment with MDMA or saline. Saline-NAc + MDMA-intraperitoneal is compared to saline-NAc + saline-intraperitoneal and OTRA-NAc + MDMA-intraperitoneal groups. Results with two OTRAs, L-368,899 and L-371,257, are pooled (n = 9 to 13). (F) Sociability after saline or MDMA in mice with selective deletion of OxtRs from SERT+ cells (n = 14 to 17). (G) Sociability in mice pretreated with saline or the 5-HT1b receptor antagonist, NAS-181, infused into the NAc before intraperitoneal treatment with MDMA (n = 11 to 12). (H) Summary time course graph showing the effect of continuous bath application of NAS-181 (20 μM) on MDMA-induced depression of NAc EPSC amplitude. Pooled data from D1 and D2 MSNs are shown. Right, sample traces, as in (B). (I) Summary graph of data in (H) (n = 5 to 8 cells, 3 to 5 mice). (J) Sociability after increasing doses of the 5-HT–releasing drug d-fenfluramine (FEN: 1, 5, and 10 mg/kg; n = 10 to 16). (K) Time course of sociability index after FEN injection (10 mg/kg; n = 11) versus saline (SAL; n = 14). (L) Effect of bath application of FEN (10 μM) on the amplitude of EPSCs recorded from NAc MSNs (n = 5, 3 mice). Top right: Sample EPSC traces taken from time points 1 and 2 as shown. Bottom right: Summary graph of FEN-mediated depression of EPSCs. Scale bars, 100 pA, 25 ms in (B) and (H); 200 pA, 25 ms in (L). Data shown are means ± SEM. Significance was determined for each comparison (statistical test): across groups (one-way ANOVA, unmatched) for (D), (E), and (J); between groups (unpaired t test) for (C), (F), (G), and (I); across group time courses (two-way ANOVA, ordinary) for (K); all planned post hoc between-group comparison (t test with Sidak correction for multiple comparisons). *P < 0.05, ***P < 0.001; ns, P > 0.05.

Supplementary Materials

  • stm.sciencemag.org/cgi/content/full/11/522/eaaw6435/DC1

    Fig. S1. Supplementary information supporting data shown in Fig. 1.

    Fig. S2. Supplementary information supporting data shown in Fig. 2D.

    Fig. S3. Supplementary information supporting data shown in Fig. 3.

    Fig. S4. Low-dose MDMA effect on EPSCs in NAc brain slices is not blocked by an OxtR antagonist.

    Table S1. Numerical and statistical data supporting Fig. 1 and fig. S1.

    Table S2. Numerical and statistical data supporting Fig. 2.

    Table S3. Numerical and statistical data supporting Fig. 3.

    Table S4. Numerical and statistical data supporting Fig. 4 and fig. S4.

    Data file S1. Raw data.

  • The PDF file includes:

    • Fig. S1. Supplementary information supporting data shown in Fig. 1.
    • Fig. S2. Supplementary information supporting data shown in Fig. 2D.
    • Fig. S3. Supplementary information supporting data shown in Fig. 3.
    • Fig. S4. Low-dose MDMA effect on EPSCs in NAc brain slices is not blocked by an OxtR antagonist.
    • Table S1. Numerical and statistical data supporting Fig. 1 and fig. S1.
    • Table S2. Numerical and statistical data supporting Fig. 2.
    • Table S3. Numerical and statistical data supporting Fig. 3.
    • Table S4. Numerical and statistical data supporting Fig. 4 and fig. S4.

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    Other Supplementary Material for this manuscript includes the following:

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