title: (+/-)-3,4-Methylenedioxymethamphetamine administration to rats does not decrease levels of the serotonin transporter protein or alter its distribution between endosomes and the plasma membrane.
abstract: We showed that the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) reduces brain tissue 5-HT, decreases expression of 5-HT transporter (SERT) protein, and increases expression of glial fibrillary acidic protein (GFAP). In contrast, doses of (+/-)-3,4-methylenedioxymethamphetamine (MDMA) that decrease brain tissue 5-HT fail to alter expression of SERT or GFAP. Using a new and highly sensitive anti-SERT antibody, we determined whether MDMA alters the subcellular distribution of SERT protein by measuring SERT expression in endosomes and plasma membranes 2 weeks after MDMA administration. Rat brain tissues (caudate, cortex, and hippocampus) were collected 3 days and 2 weeks after MDMA (7.5 mg/kg i.p., every 2 h x 3 doses) or 5,7-DHT (150 microg/rat i.c.v.) administration. Representative results from cortex are as follows. At both 3 days and 2 weeks postinjection, MDMA decreased tissue 5-HT (65%) and had no effect on GFAP expression. MDMA increased heat shock protein 32 (HSP32; a marker for microglial activation) expression (30%) at 3 days, but not 2 weeks. MDMA did not alter SERT expression at either time point and did not alter SERT levels in either endosomes or plasma membranes (2 weeks). 5,7-DHT decreased tissue 5-HT (80%), increased HSP32 expression at both time points (about 50%), and increased GFAP expression at 2 weeks (40%). 5,7-DHT decreased SERT expression (33%) at 2 weeks, but not at 3 days. These findings indicate that a dosing regimen of MDMA that depletes brain 5-HT does not alter SERT protein expression or the distribution of SERT between endosomes and the plasma membrane and does not produce detectable evidence for neurotoxicity.
authors.affiliation: Clinical Psychopharmacology Section, Intramural Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.forename: Heng
authors.initials: H
authors.lastname: Xu
authors.forename: Marisela
authors.initials: M
authors.lastname: Morales
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
mesh_terms: D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry*; D011992:Endosomes / Q000737:chemistry*; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D009457:Neuroglia / Q000737:chemistry; D009474:Neurons / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis; D050486:Serotonin Plasma Membrane Transport Proteins
chemical_list: D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D018817:N-Methyl-3,4-methylenedioxyamphetamine