Long-term effects of "ecstasy" use on serotonin transporters of the brain investigated by PET.

UNLABELLED Alterations of the serotonergic system due to ecstasy consumption have been extensively documented in recent literature. However, reversibility of these neurotoxic effects still remains unclear. To address this question, PET was performed using the serotonin transporter (SERT) ligand (11)C-(+)-McN5652 in a total of 117 subjects subdivided into 4 groups: actual ecstasy users (n = 30), former ecstasy users (n = 29), drug-naive control subjects (n = 29), and subjects with abuse of psychoactive agents other than ecstasy (n = 29). METHODS About 500 MBq (11)C-(+)-McN5652 were injected intravenously. Thirty-five scans were acquired according to a dynamic scan protocol of 90 min using a full-ring whole-body PET system. Transaxial slices were reconstructed using an iterative method. Individual brains were transformed to a template defined earlier. Distribution volume ratios (DVRs) were derived by application of a reference tissue approach for reversible binding. Gray matter of the cerebellum served as reference. SERT-rich brain regions--mesencephalon, putamen, caudate, and thalamus--were selected for the evaluation of SERT availability using volumes of interest predefined in the template. RESULTS Compared with drug-naive control subjects, the DVR in actual ecstasy users was significantly reduced in the mesencephalon (P = 0.004) and the thalamus (P = 0.044). The DVR in former ecstasy users was very close to the DVR in drug-naive control subjects in all brain regions. The DVR in polydrug users was slightly higher than that in the drug-naive control subjects in all SERT-rich regions (not statistically significant). CONCLUSION Our findings further support the hypothesis of ecstasy-induced protracted alterations of the SERT. In addition, they might indicate reversibility of the availability of SERT as measured by PET. However, this does not imply full reversibility of the neurotoxic effects.

[1]  S. Kish,et al.  Brief Communications Expedited Publication Striatal serotonin is depleted in brain of a human MDMA (Ecstasy) user , 2000 .

[2]  H. Kung,et al.  Noninvasive quantification of dopamine D2 receptors with iodine-123-IBF SPECT. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[3]  G. D. den Heeten,et al.  MDMA ("Ecstasy") and its association with cerebrovascular accidents: preliminary findings. , 2000, AJNR. American journal of neuroradiology.

[4]  V J Cunningham,et al.  11C-Diprenorphine Binding in Huntington's Disease: A Comparison of Region of Interest Analysis with Statistical Parametric Mapping , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[5]  H N Wagner,et al.  Positron Emission Tomography of 5-HT Transporter Sites in the Baboon Brain with [11C]McN5652 , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[6]  Z. Szabo,et al.  Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings , 1998, The Lancet.

[7]  E. D. De Souza,et al.  3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. , 1987, The Journal of pharmacology and experimental therapeutics.

[8]  G. Hanson,et al.  The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain. , 1986, European journal of pharmacology.

[9]  M. Kraut,et al.  Kinetic Analysis of [11C]McN5652: A Serotonin Transporter Radioligand , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[10]  J. Langston,et al.  Aminergic Metabolites in Cerebrospinal Fluid of Humans Previously Exposed to MDMA: Preliminary Observations a , 1990, Annals of the New York Academy of Sciences.

[11]  R. Buchert,et al.  Long-term effects of ‘ecstasy’ abuse on the human brain studied by FDG PET , 2001, Nuclear medicine communications.

[12]  Karl J. Friston,et al.  Statistical parametric mapping in functional neuroimaging: beyond PET and fMRI activation studies. , 1998, European journal of nuclear medicine.

[13]  R. Shank,et al.  McN-5652: a highly potent inhibitor of serotonin uptake. , 1988, The Journal of pharmacology and experimental therapeutics.

[14]  David J. Schlyer,et al.  Graphical Analysis of Reversible Radioligand Binding from Time—Activity Measurements Applied to [N-11C-Methyl]-(−)-Cocaine PET Studies in Human Subjects , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[15]  C Burger,et al.  A JAVA environment for medical image data analysis: initial application for brain PET quantitation. , 1998, Medical informatics = Medecine et informatique.

[16]  G. Gerra,et al.  Long-lasting effects of (±)3,4-methylene-dioxymethamphetamine (Ecstasy) on serotonin system function in humans , 2000, Biological Psychiatry.

[17]  Klaus P. Ebmeier,et al.  Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA (‘ecstasy’) users , 1999, British Journal of Psychiatry.

[18]  L S Seiden,et al.  Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain. , 1987, The Journal of pharmacology and experimental therapeutics.

[19]  P. Acton,et al.  Quantification of serotonin transporters in nonhuman primates using [(123)I]ADAM and SPECT. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[20]  R. Dannals,et al.  Synthesis of a radiotracer for studying serotonin uptake sites with positron emission tomography : [11C]McN-5652-Z , 1992 .

[21]  Liesbeth Reneman,et al.  Effects of dose, sex, and long-term abstention from use on toxic effects of MDMA (ecstasy) on brain serotonin neurons , 2001, The Lancet.

[22]  R. Buchert,et al.  Ecstasy – long-term effects on the human central nervous system revealed by positron emission tomography , 1999, British Journal of Psychiatry.

[23]  J. Steinbach,et al.  Synthesis of S-([18F]fluoromethyl)-(+)-McN5652 as a potential PET radioligand for the serotonin transporter. , 2001, Nuclear medicine and biology.

[24]  Marc Laruelle,et al.  Regional and subcellular localization in human brain of [3H]paroxetine binding, a marker of serotonin uptake sites , 1988, Biological Psychiatry.

[25]  M Slifstein,et al.  In vivo quantification of brain serotonin transporters in humans using [11C]McN 5652. , 2000, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[26]  J. Seibyl,et al.  Elevated central serotonin transporter binding availability in acutely abstinent cocaine-dependent patients. , 2000, The American journal of psychiatry.

[27]  U. Schmidt,et al.  The structure of McN-5652. , 2001, Bioorganic & medicinal chemistry.

[28]  G. Ricaurte,et al.  Altered Serotonin Innervation Patterns in the Forebrain of Monkeys Treated with (±)3,4-Methylenedioxymethamphetamine Seven Years Previously: Factors Influencing Abnormal Recovery , 1999, The Journal of Neuroscience.

[29]  W. van den Brink,et al.  Cortical serotonin transporter density and verbal memory in individuals who stopped using 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"): preliminary findings. , 2001, Archives of general psychiatry.

[30]  Z. Szabo,et al.  In vivo detection of short‐ and long‐term MDMA neurotoxicity—a positron emission tomography study in the living baboon brain , 1998, Synapse.

[31]  M. Gill,et al.  Agony and ecstasy: a review of MDMA effects and toxicity , 2000, European Psychiatry.

[32]  Simon M. Ametamey,et al.  Evaluation of Serotonergic Transporters using PET and [11C](+)McN-5652: Assessment of Methods , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[33]  Zsolt Szabo,et al.  Positron emission tomography imaging of serotonin transporters in the human brain using [11C](+)McN5652 , 1995, Synapse.

[34]  W. van den Brink,et al.  Memory disturbances in ”Ecstasy” users are correlated with an altered brain serotonin neurotransmission , 2000, Psychopharmacology.

[35]  C. Rorden,et al.  Stereotaxic display of brain lesions. , 2000, Behavioural neurology.

[36]  John L. Musachio,et al.  Positron emission tomography of 5-HT reuptake sites in the human brain with C-11 McN5652 extraction of characteristic images by artificial neural network analysis , 1995, Behavioural Brain Research.

[37]  J. Andersson,et al.  Accurate attenuation correction despite movement during PET imaging. , 1995, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[38]  G. Battaglia,et al.  Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.