title: Sustained recreational use of ecstasy is associated with altered pre and postsynaptic markers of serotonin transmission in neocortical areas: a PET study with [¹¹C]DASB and [¹¹C]MDL 100907.
abstract: 3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT(2A) receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT(2A) receptors. Positron emission tomography studies using the SERT ligand [¹¹C]DASB and the 5-HT(2A) receptor ligand [¹¹C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT(2A) receptor availability (binding potential, BP(ND)) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP(ND) and higher 5-HT(2A) receptor BP(ND) in cortical, but not subcortical regions. Decreased SERT BP(ND) was regionally associated with upregulated 5-HT(2A) receptor BP(ND). In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.
authors.affiliation: Department of Psychiatry, Columbia University, New York State Psychiatric Institute, New York, NY 10032, USA. nu2118@columbia.edu
authors.forename: Nina Bl
authors.initials: NB
authors.lastname: Urban
authors.forename: Ragy R
authors.initials: RR
authors.lastname: Girgis
authors.forename: Peter S
authors.initials: PS
authors.lastname: Talbot
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Kegeles
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.forename: W Gordon
authors.initials: WG
authors.lastname: Frankle
authors.forename: Carl L
authors.initials: CL
authors.lastname: Hart
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.forename: Anissa
authors.initials: A
authors.lastname: Abi-Dargham
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
mesh_terms: D000328:Adult; D019969:Amphetamine-Related Disorders / Q000000981:diagnostic imaging / Q000473:pathology*; D001596:Benzylamines / Q000493:pharmacokinetics*; D001931:Brain Mapping; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D005260:Female; D005464:Fluorobenzenes / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D019579:Neocortex / Q000000981:diagnostic imaging* / Q000187:drug effects; D010880:Piperidines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000493:pharmacokinetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D001596:Benzylamines; D002250:Carbon Radioisotopes; D005464:Fluorobenzenes; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; C079049:volinanserin