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

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.

Effects of the selective neurotensin antagonist SR 142948A on 3,4-methylenedioxymethamphetamine-induced behaviours in mice

“…At the cellular level MDMA administration in mice causes a variety of transcriptional events, probably responsible for the long term effects and the addictive properties of this substance, in several brain structures (Salzmann et al, 2006;Salzmann et al, 2003). Among these, up-regulation of the gene coding for the precursor of the peptide neurotensin was recently observed in our laboratory in mice striatum (Salzmann et al, 2006). It is well known that this tridecapeptide is closely related with dopamine transmission in the central nervous system.…”

“…Moreover, MDMA displays a moderate affinity also to other receptors, whose activation could be at the origin of some of its effects (Battaglia et al, 1988). At the cellular level MDMA administration in mice causes a variety of transcriptional events, probably responsible for the long term effects and the addictive properties of this substance, in several brain structures (Salzmann et al, 2006;Salzmann et al, 2003). Among these, up-regulation of the gene coding for the precursor of the peptide neurotensin was recently observed in our laboratory in mice striatum (Salzmann et al, 2006).…”

FosB Null Mutant Mice Show Enhanced Methamphetamine Neurotoxicity: Potential Involvement of FosB in Intracellular Feedback Signaling and Astroglial Function

“…Fos target genes involved in such a general negative feedback might be found more easily than Fos target genes that have more specific functions in certain neuronal types. Indeed, all previous studies that have detected attenuated RGK induction in Fos-gene-targeted mice (Cadet et al, 2002;Kuroda et al, 2007;Salzmann et al, 2006) used grossly dissected brain tissue, containing different neuronal populations.…”

“…For instance, c-Fos heterozygous mutant ( + /À) mice, in which METH-induced dopaminergic terminal damage and neuronal apoptosis are exacerbated (Deng et al, 1999), show significant impairment in GEM (a member of RGK family) upregulation in the striatum compared with wild-type mice on METH administration (Cadet et al, 2002). Administration of MDMA causes ERK activation and subsequent upregulation of REM2, another member of RGK, along with c-Fos and FosB in the striatum (Salzmann et al, 2006). Induction of FosB and REM2, but not c-Fos by MDMA is blocked by SL327, a specific inhibitor of ERK phosphorylation (Salzmann et al, 2006).…”

“…Administration of MDMA causes ERK activation and subsequent upregulation of REM2, another member of RGK, along with c-Fos and FosB in the striatum (Salzmann et al, 2006). Induction of FosB and REM2, but not c-Fos by MDMA is blocked by SL327, a specific inhibitor of ERK phosphorylation (Salzmann et al, 2006).…”