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. 2006;137(2):473-82.
doi: 10.1016/j.neuroscience.2005.09.019. Epub 2005 Nov 14.

Analysis of transcriptional responses in the mouse dorsal striatum following acute 3,4-methylenedioxymethamphetamine (ecstasy): identification of extracellular signal-regulated kinase-controlled genes

J Salzmann  1 , C Canestrelli, F Noble, C Marie-Claire
Affiliations

Analysis of transcriptional responses in the mouse dorsal striatum following acute 3,4-methylenedioxymethamphetamine (ecstasy): identification of extracellular signal-regulated kinase-controlled genes

J Salzmann et al. Neuroscience. 2006.

Abstract

3,4-Methylenedioxymethamphetamine (ecstasy), a widely used recreational drug with psychoactive properties, induces both serotonin and dopamine release in the brain. However, little is known about its intracellular effects. We previously showed that 3,4-methylenedioxymethamphetamine rewarding effects in mice were dependent upon extracellular signal-regulated kinase activation and that dorsal striatum was a critical region for mediating extracellular signal-regulated kinase-dependent Egr1 3,4-methylenedioxymethamphetamine-induced transcription. Here, we extend these findings by showing that 3,4-methylenedioxymethamphetamine is indeed able to activate extracellular signal-regulated kinase within this structure. To identify genes regulated by acute 3,4-methylenedioxymethamphetamine in the mice dorsal striatum, and selectively controlled by this kinase, we performed microarray experiments by using a selective inhibitor of extracellular signal-regulated kinase activation, SL327. Of the approximately 24,000 genes from the microarray, 27 showed altered expression after exposure to 3,4-methylenedioxymethamphetamine, and among these, 59% were partially or totally inhibited by SL327 pretreatment. Our results showed that the genes regulated by 3,4-methylenedioxymethamphetamine encode proteins that belong to transcription factors family, signaling pathways (phosphatases, cytoskeleton regulation), and synaptic functions. These early changes, and especially those controlled by extracellular signal-regulated kinase activation might play significant roles in the expression of many of the behaviors that occur following 3,4-methylenedioxymethamphetamine taking.

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Figures

Figure 1
Figure 1
Western-blot analysis of the effects of an acute MDMA injection (9 mg/kg; i.p.) ± SL327 (50 mg/kg; i.p.) on pERK expression in the dorsal striatum. SL327 was administered 1 hour before MDMA and mice were killed 10 minutes after the last injection (see methods for details). Data were expressed as a percentage of vehicle-treated mice and represent means ± SEM of pERK/total ERK optical density for the isoform ERK2 (n = 7 – 8/group). A representative immunoblot is presented above the histograms. Statistical analysis was done by ANOVA, followed by a Newman-Keuls Multiple Comparison Test. * p<0.05 compared to control group. ### p<0.001 compared to MDMA alone.
Figure 2
Figure 2
Real time quantitative PCR confirmation of SL327 ± MDMA induced changes in 8 transcripts. SL327 was administered 1 hour before MDMA and mice were killed 2 hours after the last injection. The mRNA levels were measured as fluorescent intensities using quantitative real-time PCR and normalized to Hprt mRNA levels (see methods for details). Values represent means ± SEM (percentage of vehicle-treated animals; n = 10 – 12/group). Statistical analysis was done by ANOVA, followed by Fisher’s PLSD. * p<0.05, ** p<0.01 and *** p<0.001 compared to control group. # p<0.05, ## p<0.01 and ### p<0.001 compared to MDMA alone.
Figure 3
Figure 3
Real time quantitative PCR analysis of SL327 ± MDMA treatment effect on Rem2 transcription. SL327 was administered 1 hour before MDMA and mice were killed 2 hours after the last injection. The mRNA levels were measured as fluorescent intensities using quantitative real-time PCR and normalized to Hprt mRNA levels (see methods for details). Values represent means ± SEM (percentage of vehicle-treated animals; n = 12/group). Statistical analysis was done by ANOVA, followed by Fisher’s PLSD. * p<0.05 compared to control group. #p<0.05 compared to MDMA alone.
Figure 4
Figure 4
Kinetics of the effect of MDMA treatment on Rhoe, Rem2, Dnajb5 and Nts transcription. Mice were killed 2, 4 and 6 hours after MDMA injection. The mRNA levels were measured as fluorescent intensities using quantitative real-time PCR and normalized to Hprt mRNA levels (see methods for details). Values represent fold change as compared to vehicle-treated animals at each time point (n = 12/group). Statistical analysis was done by Student’s test. * p<0.05, ** p<0.01 and *** p<0.001 compared to control.
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