Figure 3. NAc 5-HT_2C receptors calibrate MDMA reward.

a. Genetic strategy for conditional deletion of SERT.

b. Effect of SERT deletion on 3-chamber social preference with MDMA (7.5 mg/kg). Unpaired, two-tailed t-test, t₂₆ = 2.473, *p = 0.0203.

c. SERT deletion enhanced CPP for MDMA with a subthreshold dose (5 mg/kg). Two-way, repeated measures ANOVA, time x genotype interaction F_1,25 = 6.506, **p = 0.0027. Sidak’s multiple comparisons test, Pre vs Post: WT p = 0.9083, KO ***p = 0.0007, WT vs KO: Pre p = 0.6565, Post **p = 0.0032.

d. Summary and direct comparison of CPP performance. Unpaired, two-tailed t-test, t₂₅ = 3.098, **p = 0.0048.

e. Experimental setup of microinfusions before subthreshold MDMA CPP.

f. Effects of microinfusing each compound into the NAc on subthreshold MDMA CPP. Vehicle: paired, two-tailed t-test, t₁₄ = 0.8939, p = 0.3865. Escitalopram (Scit): paired, two-tailed t-test, t₁₀ = 4.385, **p = 0.0014. NAS-181: paired, two-tailed t-test, t₉ = 0.2167, p = 0.8833. SB24: paired, two-tailed t-test, t₉ = 5.220, ***p = 0.0003.

g. Summary and direct comparison of CPP performance. Ordinary one-way ANOVA, F_3,44 = 7.265, ***p = 0.0005. Dunnett’s multiple comparisons test, vehicle vs Scit **p = 0.0039, vehicle vs NAS-181 p = 0.9745, vehicle vs SB24 **p = 0.0084.

h. Schematic of photometry recording setup for dual drug microinfusions into the NAc. Top right, experimental schedule. Scale = 100 um.

i. Effect of intra-NAc infusion of Scit on bulk DA release evoked by MDMA (5 mg/kg).

j. Effect of intra-NAc infusion of NAS-181 on bulk DA release evoked by MDMA (5 mg/kg).

k. Effect of intra-NAc infusion of SB24 on bulk DA release evoked by MDMA (5 mg/kg).

l. Effect of intra-NAc infusions of Scit and SB24 on bulk DA release after an injection of saline.

m. Summary data of bulk DA levels after infusion of each compound. Ordinary one-way ANOVA, F_5,36 = 14.54, ****p < 0.0001. Dunnett’s multiple comparisons test, vehicle vs Scit ****p < 0.0001, vehicle vs NAS-181 p = 0.9998, vehicle vs SB24 **p = 0.0049, vehicle vs Scit + saline p = 0.6553, vehicle vs SB24 + saline p = 0.4897.