Effects of 3,4‐methylenedioxymethamphetamine (MDMA) on serotonin transporter and vesicular monoamine transporter 2 protein and gene expression in rats: implications for MDMA neurotoxicity

MDMA (Ecstasy) causes substantial regulatory changes in serotonergic markers in rats, questioning the need to invoke distal axotomy as an explanation for MDMA-related serotonergic deficits. In adult male Sprague-Dawley rats, MDMA treatment produced large reductions in serotonin transporter (SERT) levels across all brain regions examined, but little change in vesicular monoamine transporter 2 (VMAT-2) protein expression in the hippocampus when noradrenergic input was lesioned beforehand. MDMA also caused a striking decrease in SERT gene expression and a lesser effect on VMAT-2 in raphe tissue. These findings suggest MDMA's effects involve regulatory changes rather than just nerve terminal damage.

Study at a glance

Abstract

J. Neurochem. (2009) 112 , 951–962. Abstract 3,4‐Methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) is a popular recreational drug used worldwide. This study aimed to determine the effects of this compound on the expression of nerve terminal serotonergic markers in rats. Experiment 1 investigated MDMA‐induced changes in levels of the serotonin transporter (SERT) and the vesicular monoamine transporter 2 (VMAT‐2) in the hippocampus, a region with sparse dopaminergic innervation, after lesioning noradrenergic input with N ‐(2‐chloroethyl)‐ N ‐ethyl‐2‐bromobenzylamine (DSP‐4). Adult male Sprague–Dawley rats were administered 100 mg/kg DSP‐4 or saline 1 week prior to either an MDMA (10 mg/kg × 4) or saline binge. Two weeks following the binge treatment, the DSP‐4/MDMA group unexpectedly showed little change in hippocampal VMAT‐2 protein expression compared with DSP‐4/Saline controls, despite large reductions in SERT levels in all regions examined in the MDMA‐treated animals. Furthermore, animals treated with binge MDMA (Experiment 2) showed a striking decrease in SERT gene expression (and a lesser effect on VMAT‐2) measured by quantitative RT‐PCR in pooled dorsal and median raphe tissue punches, when compared with saline‐treated controls. These results demonstrate that MDMA causes substantial regulatory changes in the expression of serotonergic markers, thus questioning the need to invoke distal axotomy as an explanation of MDMA‐related serotonergic deficits.