Effect of 5-HT2B receptor inhibition on locomotor activity and behavioral sensitization after MDMA injection.

<p><b>Locomotor sensitization after MDMA two-injection protocol in WT and 5-HT_2B^−/− mice (A–D):</b> 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 <b>A</b>) or RS127445-treated WT mice <b>B</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 <b>A</b>) or RS127445 pre-treated WT mice <b>B</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 <b>C</b>). MDMA (30 mg/kg i.p.) induces locomotor activity after the first injection in WT and 5-HT_2B^−/− mice compared to saline injection <b>D</b>). 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 <b>D</b>). Data (means±SEM, <i>n</i> = 8−14 per group) were analyzed by two-way ANOVA with genotype (<b>A–D</b>) or RS127445 pre-treatment (<b>B–C</b>) and MDMA treatment as main factors. A significant interaction was observed for the locomotor activity in figure <b>A</b>) <i>F</i> (2,66) = 12.86 <i>p</i><0.01, and <b>B</b>) <i>F</i> (2,54) = 11.49 <i>p</i><0.01, as well as a main effect of genotype <i>F</i> (2, 66) = 15.68, p<0.001 (<b>A</b>) or RS127445 pre-treatment <i>F</i> (2, 54) = 10.24, p<0.05 (<b>B</b>) and of MDMA treatment <i>F</i> (1,66) = 9.26, p<0.001 (<b>A</b>), and <i>F</i> (1,54) = 17.04, p<0.001 (<b>B</b>). No significant interaction was observed for the locomotor activity in figure <b>C</b>) <i>F</i> (2,66) = 3.57, ns, whereas a main effect of RS127445 pre-treatment at the 1^st MDMA injection, <i>F</i> (2,66) = 28.56, p<0.001, and of MDMA treatment <i>F</i> (1,66) = 6.64, p<0.01 were detected. Neither a significant interaction, <i>F</i> (2,50) = 0.25, ns, nor a main effect of genotype <i>F</i> (1,50) = 0.9, ns, was observed for the locomotor activity in figure <b>D</b>), whereas a main effect of MDMA treatment, <i>F</i> (2,50) = 82.72, <i>p</i><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. <b>Locomotor sensitization after repeated MDMA injection in WT and 5-HT_2B^−/− mice (E):</b> 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, <i>n</i> = 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.