Effect of repeated exposure to MDMA on the function of the 5-HT transporter as assessed by synaptosomal 5-HT uptake

Abstract

Recent studies have demonstrated that a preconditioning regimen (i.e., repeated low doses) of MDMA provides protection against the reductions in tissue concentrations of 5-HT and 5-HT transporter (SERT) density and/or expression produced by a subsequent binge regimen of MDMA. In the present study, the effects of preconditioning and binge treatment regimens of MDMA on SERT function were assessed by synaptosomal 5-HT uptake. Synaptosomal 5-HT uptake was reduced by 72% 7 days following the binge regimen (10 mg/kg, ip every 2 hr for a total of 4 injections). In rats exposed to the preconditioning regimen of MDMA (daily treatment with 10 mg/kg for 4 days), the reduction in synaptosomal 5-HT uptake induced by a subsequent binge regimen was significantly less. Treatment with the preconditioning regimen alone resulted in a transient 46% reduction in 5-HT uptake that was evident 1 day, but not 7 days, following the last injection of MDMA. Furthermore, the preconditioning regimen of MDMA did not alter tissue concentrations of 5-HT, whereas the binge regimen of MDMA resulted in a long-term reduction of 40% of tissue 5-HT concentrations. The distribution of SERT immunoreactivity (ir) in membrane and endosomal fractions of the hippocampus also was evaluated following the preconditioning regimen of MDMA. There was no significant difference in the relative distribution of SERTir between these two compartments in control and preconditioned rats. The results demonstrate that SERT function is transiently reduced in response to a preconditioning regimen of MDMA, while long-term reductions in SERT function occur in response to a binge regimen of MDMA. Moreover, a preconditioning regimen of MDMA provides protection against the long-term reductions in SERT function evoked by a subsequent binge regimen of the drug. It is tempting to speculate that the neuroprotective effect of MDMA preconditioning results from a transient down-regulation in SERT function.

Adolescent MDMA Exposure Diminishes the Physiological, Behavioral, and Neurotoxic Consequences of a Subsequent Methamphetamine Binge

“…Several factors have received significant attention regarding the mechanisms underlying substituted amphetamine preconditioning. Evidence has been presented for a variety of potentially relevant cellular/biochemical/molecular changes [9,11,19,21,29,36,44,60,61,70]. But until additional research is conducted, it will remain unclear whether these changes work in concert or whether there are multiple pathways leading to the neuroprotective effects of low-dose MDMA or METH administration.…”

Monoamine Neurotransmitters and Drug Addiction

“…Ecstasy (3,4-methylenedioxymethamphetamine, or MDMA) can cause synaptic 5-HT release, induce heat production and hyperactivity, deplete 5-HT, and damage nerve terminal structures (14). If MDMA was used five times within 24 hours, the concentration of 5-HT would not recover until 110 days later (15). Studies have shown that acute administration of MDMA affects the normal synthesis, operation, and metabolism of 5-HT by changing the expression of 5-HT-related genes (16).…”

Analysis of membrane transport mechanisms of endogenous substrates using chromatographic techniques

“…Most studies on the evaluation of serotonin transport via SLC6A3, SLC6A4/5‐HTT/SERT, SLC18A2 and SLC22A3 by chromatographic techniques have used HPLC–EC, usually with an octadecylsilyl (C 18 ) column (Table ). Serotonin has been determined in brain dialysates, cochlear supernatants, plasma and various tissues by HPLC–EC (Armando et al, ; Callaghan et al, ; Cedeño et al, ; Choi et al, ; Fazzino et al, ; Feng et al, ; Huff et al, ; Kim et al, ; Kish et al, ; Kreiss et al, ; Linder et al, , , ; Nakatani et al, ; Ni et al, ; Ni et al, ; Pazzagli et al, ; Reader et al, ; Ren‐Patterson et al, ; Sánchez et al, ; Taylor et al, ; Tsuruoka et al, ; Vicente‐Torres et al, ; Vogel et al, ; Wei et al, ; Zhang et al, ; Zhou et al, ) and by HPLC–FL (Huang et al, ). Fanzzino et al demonstrated serotonin determination in human monocytes and lymphocytes (Fazzino et al, ).…”