Effects of 3,4-methylenedioxymethamphetamine (MDMA) on serotonin transporter and vesicular monoamine transporter 2 protein and gene expression in rats: implications for MDMA neurotoxicity.
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 x 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.
Biezonski
Dominik K
DK
Neuroscience and Behavior Program, University of Massachusetts, Amherst, Massachusetts, USA.
Meyer
Jerrold S
JS
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001596:Benzylamines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000697:Central Nervous System Stimulants / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006213:Hallucinogens / Q000633:toxicity*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D011247:Pregnancy; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
D001596:Benzylamines; D000697:Central Nervous System Stimulants; D006213:Hallucinogens; D014179:Neurotransmitter Uptake Inhibitors; D050486:Serotonin Plasma Membrane Transport Proteins; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D008694:Methamphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; C012102:DSP 4