3,4-Methylenedioxymethamphetamine Induces Gene Expression Changes in Rats Related to Serotonergic and Dopaminergic Systems, But Not to Neurotoxicity

Abstract

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is an amphetamine derivative widely abused by young adults. Although many studies have reported that relatively high doses of MDMA deplete serotonin (5-HT) content and decrease the availability of serotonin transporters (5-HTT), limited evidence is available as to the adaptive mechanisms taking place in gene expression levels in the brain following a dosing regimen of MDMA comparable to human consumption. In order to further clarify this issue, we used quantitative PCR to study the long-term changes induced by acute administration of MDMA (5 mg/kg × 3) in the expression of genes related to serotonergic and dopaminergic systems, as well as those related to cellular toxicity in the cortex, hippocampus, striatum, and brain stem of rats. Seven days after MDMA administration, we found a significantly lower expression of the 5-HTT (Slc6a4) and the vesicular monoamine transporter (Slc18a2) genes in the brain stem area. In the hippocampus, monoamine oxidase B (Maob) and tryptophan hydroxylase 2 (Tph2) gene expressions were increased. In the striatum, tyrosine hydroxylase (Th) expression was decreased, and a lower expression of α-synuclein (Snca) was observed in the cortex. In contrast, no significant changes were observed in the genes considered to be biomarkers of toxicity including the glial fibrillary acidic protein (Gfap) and the heat-shock 70 kD protein 1A (Hspa1a) in any of the structures assayed. These results suggest that MDMA promotes adaptive changes in genes related to serotonergic and dopaminergic functionality, but not in genes related to neurotoxicity.

Serotonergic impairment and memory deficits in adolescent rats after binge exposure of methylone

“…Conversely, they found an increase in the expression levels of the TPH-2 gene (Cuyas et al, 2014). Both regulations are considered a compensatory mechanism in order to overcome the decrease in 5-HT induced by MDMA treatment.…”

“…Moreover, other authors (Cuyas et al, 2014; Kirilly et al, 2008) have suggested that brain SERT gene expression may be negatively regulated seven days after MDMA exposure, which could lead to a reduction in paroxetine binding in the absence of physical damage. Conversely, they found an increase in the expression levels of the TPH-2 gene (Cuyas et al, 2014). Both regulations are considered a compensatory mechanism in order to overcome the decrease in 5-HT induced by MDMA treatment.…”

Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse

“…MDMA pretreatment decreased 5HT tissue levels in various brain regions (Cuyas et al, 2014), serotonin transporter (SERT) expression (Shankaran & Gudelsky, 1999;Vegting et al, 2016) and vesicular monoamine transporter-2 (VMAT-2) expression (Biezonski & Meyer, 2010). MDMA self-administration decreased MDMAstimulated 5HT overflow, as measured by in vivo microdialysis (Reveron et al, 2010a) and decreased SERT binding as measured by autoradiography (Schenk et al, 2007).…”

Ecstasy Neurotoxicity

“…Many studies have demonstrated that MDMA is neurotoxic to serotoninergic neurons of the hippocampus (16,17). These effects seem to be dose-dependent, leading to memory impairment (18) and apoptosis in the hippocampus (19).…”