Psychopharmacology

, 200:439

Positron emission tomographic studies of brain dopamine and serotonin transporters in abstinent (±)3,4-methylenedioxymethamphetamine (“ecstasy”) users: relationship to cognitive performance

  • Una D. McCann
  • Zsolt Szabo
  • Melin Vranesic
  • Michael Palermo
  • William B. Mathews
  • Hayden T. Ravert
  • Robert F. Dannals
  • George A. Ricaurte
Original Investigation
  • 357 Downloads

Abstract

Background

(±)3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a recreational drug and brain serotonin (5-HT) neurotoxin. Under certain conditions, MDMA can also damage brain dopamine (DA) neurons, at least in rodents. Human MDMA users have been found to have reduced brain 5-HT transporter (SERT) density and cognitive deficits, although it is not known whether these are related. This study sought to determine whether MDMA users who take closely spaced sequential doses, which engender high plasma MDMA concentrations, develop DA transporter (DAT) deficits, in addition to SERT deficits, and whether there is a relationship between transporter binding and cognitive performance.

Materials and methods

Sixteen abstinent MDMA users with a history of using sequential MDMA doses (two or more doses over a 3- to 12-h period) and 16 age-, gender-, and education-matched controls participated. Subjects underwent positron emission tomography with the DAT and SERT radioligands, [11C]WIN 35,428 and [11C]DASB, respectively. Subjects also underwent formal neuropsychiatric testing.

Results

MDMA users had reductions in SERT binding in multiple brain regions but no reductions in striatal DAT binding. Memory performance in the aggregate subject population was correlated with SERT binding in the dorsolateral prefrontal cortex, orbitofrontal cortex, and parietal cortex, brain regions implicated in memory function. Prior exposure to MDMA significantly diminished the strength of this relationship.

Conclusions

Use of sequential MDMA doses is associated with lasting decreases in brain SERT, but not DAT. Memory performance is associated with SERT binding in brain regions involved in memory function. Prior MDMA exposure appears to disrupt this relationship. These data are the first to directly relate memory performance to brain SERT density.

Keywords

Positron emission tomography Amphetamines Pharmacokinetics Neurotoxicity Serotonin Dopamine Memory 

References

  1. Berg EA (1948) A simple objective technique for measuring flexibility in thinking. J Gen Psych 39:15–22Google Scholar
  2. Bhattachary S, Powell JH (2001) Recreational use of 3,4 methylenedioxymethamphetamine (MDMA) or ‘ecstasy’: evidence for cognitive impairment. Psychol Med 31:647–658PubMedCrossRefGoogle Scholar
  3. Bolla KI, McCann UD, Ricaurte GA (1998) Impaired memory function in abstinent MDMA (“ecstasy”) users. Neurology 51:1532–1537PubMedGoogle Scholar
  4. Buchert R, Thomasius R, Nebeling B, Petersen K, Obrocki J, Jenicke L, Wilke F, Wartberg L, Zapletalova P, Clausen M (2003) Long-term effects of “ecstasy” use on serotonin transporters of the brain investigated by PET. J Nucl Med 44:375–384PubMedGoogle Scholar
  5. Buchert R, Thomasius R, Wilke F, Petersen K, Nebeling B, Obrocki J, Schulze O, Schmidt U, Clausen M (2004) A voxel-based PET investigation of the long-term effects of “ecstasy” consumption on brain serotonin transporters. Am J Psychiatry 161:1181–1189PubMedCrossRefGoogle Scholar
  6. Chu T, Kumagai Y, DiStefano EW, Cho AK (1996) Disposition of methylenedioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion. Biochem Pharmacol 51:789–796PubMedCrossRefGoogle Scholar
  7. Commins DL, Vosmer G, Virus RM, Woolverton WL, Schuster CR, Seiden LS (1987) Biochemical and histological evidence that methylenedioxymethylamphetamine MDMA) is toxic to neurons in the rat brain. J Pharmacol Exp Ther 241:338–345PubMedGoogle Scholar
  8. Dafters RI, Hoshi R, Talbot AC (2004) Contribution of cannabis and MDMA (“ecstasy”) to cognitive changes in long-term polydrug users. Psychopharmacology (Berl) 173:405–410CrossRefGoogle Scholar
  9. Dannals R, Neumeyer J, Milius R, Ravert H, Wilson A, Wagner H (1993) Synthesis of a radiotracer for studying dopamine uptake sites in vivo using PET: 2b-carbomethoxy-3b-(4-fluorophenyl)-[N-11C-methyl]tropane ([11C]WIN-35,428). J Label Compd Radiopharm 33:147–153CrossRefGoogle Scholar
  10. de la Torre R, Farre M, Ortuno J, Mas M, Brenneisen R, Roset PN, Segura J, Cami J (2000) Non-linear pharmacokinetics of MDMA (‘ecstasy’) in humans. Br J Clin Pharmacol 49:104–109PubMedCrossRefGoogle Scholar
  11. Easton N, Marsden CA (2006) Ecstasy: are animal data consistent between species and can they translate to humans? J Psychopharmacol 20:194–210PubMedCrossRefGoogle Scholar
  12. El-Mallakh RS, Abraham HD (2007) MDMA (ecstasy). Ann Clin Psychiatry 19:45–52PubMedCrossRefGoogle Scholar
  13. First MB, Spitzer RL, Gibbon M, Williams JB (1997) Structured clinical interview for DSM-IV axis I disorders (SCID-I), clinician version. American Psychiatric, Arlington, VAGoogle Scholar
  14. Fox HC, Toplis AS, Turner JJD, Parrott AC (2001) Auditory verbal learning in drug-free ecstasy polydrug users. Hum Psychopharmacol 16:613–618PubMedCrossRefGoogle Scholar
  15. Frankle WG, Slifstein M, Gunn RN, Huang Y, Hwang DR, Darr EA, Narendran R, Abi-Dargham A, Laruelle M (2006) Estimation of serotonin transporter parameters with 11C-DASB in healthy humans reproducibility and comparison of methods. J Nucl Med 47:815–826PubMedGoogle Scholar
  16. Gouzoulis-Mayfrank E, Daumann J, Tuchtenhagen F, Pelz S, Becker S, Kunert H, Fimm B, Sass H (2000) Impaired cognitive impairment in drug free users of recreational ecstasy. J Neurol Neurosurg Psychiatry 68:719–725PubMedCrossRefGoogle Scholar
  17. Green AR, Mechan AO, Elliott JM, O’Shea E, Colado MI (2003) The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev 55:463–508PubMedCrossRefGoogle Scholar
  18. Heinz A, Jones DW (2000) Serotonin transporters in ecstasy users. Br J Psychiatry 176:193–195PubMedCrossRefGoogle Scholar
  19. Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, Holden J, Houle S, Huang SC, Ichise M, Iida H, Ito H, Kimura Y, Koeppe RA, Knudsen GM, Knuuti J, Lammertsma AA, Laruelle M, Logan J, Maguire RP, Mintun MA, Morris ED, Parsey R, Price JC, Slifstein M, Sossi V, Suhara T, Votaw JR, Wong DF, Carson RE (2007) Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cerebr Blood Flow Metab 27:1533–1539CrossRefGoogle Scholar
  20. Kalechstein AD, De La Garza R 2nd, Mahoney JJ 3rd, Fantegrossi WE, Newton TF (2007) MDMA use and neurocognition: a meta-analytic review. Psychopharmacology 189:531–537PubMedCrossRefGoogle Scholar
  21. Kerenyi L, Ricaurte GA, Schretlen DJ, McCann U, Varga J, Mathews WB, Ravert HT, Dannals RF, Hilton J, Wong DF, Szabo Z (2003) Positron emission tomography of striatal serotonin transporters in Parkinson disease. Arch Neurol 60:1223–1229PubMedCrossRefGoogle Scholar
  22. Lamers CT, Bechara A, Rizzo M, Ramaekers JG (2006) Cognitive function and mood in MDMA/THC users, THC users and non-drug using controls. J Psychopharmacol 20:302–311PubMedCrossRefGoogle Scholar
  23. Laruelle M (2000) The role of model-based methods in the development of single scan techniques. Nucl Med Biol 27:637–642PubMedCrossRefGoogle Scholar
  24. Laruelle M, Baldwin RM, Mallison RT, Zea Ponce Y, Zoghbi SS, Al-Tikriti MS, Sybirska EH, Zimmermann RC, Wisniewski G, Neumeyer JL, Milius RA, Wan S, Smith EO, Roth RH, Charney DS, Hoffer PB, Innis RB (1993) SPECT imaging of dopamine and serotonin transporters with 123I beta-CIT: pharmacological characterization of brain uptake in nonhuman primates. Synapse 13:295–309PubMedCrossRefGoogle Scholar
  25. Marquardt DW (1963) An algorithm for least-squares estimation of non-linear parameters. J Soc Ind Appl Math 11:431–441CrossRefGoogle Scholar
  26. McCann UD, Szabo Z, Scheffel U, Dannals RF, Ricaurte GA (1998) Positron emission tomographic evidence of toxic effect of MDMA (“ecstasy”) on brain serotonin neurons in human beings. Lancet 352:1433–1437PubMedCrossRefGoogle Scholar
  27. McCann UD, Ricaurte GA, Molliver ME (2001) “Ecstasy” and serotonin neurotoxicity: new findings raise more questions. Arch Gen Psychiatry 58:907–908PubMedCrossRefGoogle Scholar
  28. McCann UD, Szabo Z, Seckin E, Rosenblatt P, Mathews WB, Ravert HT, Dannals RF, Ricaurte GA (2005) Quantitative PET studies of the serotonin transporter in MDMA users and controls using [11C]McN5652 and [11C]DASB. Neuropsychopharmacology 30:1741–1750PubMedCrossRefGoogle Scholar
  29. McCann UD, Peterson SC, Ricaurte GA (2007) The effect of catecholamine depletion by alpha-methyl-para-tyrosine on measures of cognitive performance and sleep in abstinent MDMA users. Neuropsychopharmacology 32(8):1695–706PubMedCrossRefGoogle Scholar
  30. Mechan A, Yuan J, Hatzidimitriou G, Irvine RJ, McCann UD, Ricaurte GA (2006) Pharmacokinetic profile of single and repeated oral doses of MDMA in squirrel monkeys: relationship to lasting effects on brain serotonin neurons. Neuropsychopharmacology 31:339–350PubMedCrossRefGoogle Scholar
  31. Morgan MJ, McFie L, Fleetwood LH, Robinson J (2002) Ecstasy (MDMA): are the psychological problems associated with its use reversed by prolonged abstinence? Psychopharmacology 159:294–303PubMedCrossRefGoogle Scholar
  32. Parrott AC (2005) Chronic tolerance to recreational MDMA (3,4-methylenedioxymethamphetamine) or ecstasy. J Psychopharmacol 19:71–83PubMedCrossRefGoogle Scholar
  33. Reitan RM, Wolfson D (1993) The Halstead–Reitan neuropsychological test battery: theory and clinical interpretation. Neuropsychology, Tucson, AZGoogle Scholar
  34. Reneman L, Booij J, Schmand B, van den Brink W, Gunning B (2000) Memory disturbances in “ecstasy” users are correlated with an altered brain serotonin neurotransmission. Psychopharmacology 148:322–324PubMedCrossRefGoogle Scholar
  35. Reneman L, Lavalaye J, Schmand B, de Wolff FA, van den Brink W, den Heeten GJ, Booij J (2001) Cortical serotonin transporter density and verbal memory in individuals who stopped using 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”): preliminary findings. Arch Gen Psychiatry 58:901–906PubMedCrossRefGoogle Scholar
  36. Rey A (1964) L’examen clinicque en psychologie. Presses Universitaires de France, ParisGoogle Scholar
  37. Schilt T, de Win MM, Koeter M, Jager G, Korf DJ, van den Brink W, Schmand B (2007) Cognition in novice ecstasy users with minimal exposure to other drugs: a prospective cohort study. Arch Gen Psychiatry 64(6):728–736PubMedCrossRefGoogle Scholar
  38. Semple DM, Ebmeier KP, Glabus MF, O’Carroll RE, Johnstone EC (1999) Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA (‘ecstasy’) users. Br J Psychiatry 175:63–69PubMedCrossRefGoogle Scholar
  39. Steele TD, McCann UD, Ricaurte GA (1994) 3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”): pharmacology and toxicology in animals and humans. Addiction 89(5):539–551PubMedCrossRefGoogle Scholar
  40. Stroop JR (1935) Studies of interference in serial verbal reactions. J Exp Psychol 18:643–661CrossRefGoogle Scholar
  41. Szabo Z, Scheffel U, Mathews WB, Ravert HT, Szabo K, Kraut M, Palmon S, Ricaurte GA, Dannals RF (1999) Kinetic analysis of [11C]McN5652: a serotonin transporter radioligand. J Cereb Blood Flow Metab 19:967–981PubMedCrossRefGoogle Scholar
  42. Szabo Z, McCann UD, Wilson AA, Scheffel U, Owonikoko T, Mathews WB, Ravert HT, Hilton J, Dannals RF, Ricaurte GA (2002) Comparison of (+)-(11)C-McN5652 and (11)C-DASB as serotonin transporter radioligands under various experimental conditions. J Nucl Med 43:678–692PubMedGoogle Scholar
  43. Thomasius R, Petersen K, Buchert R, Andresen B, Zapletalova P, Wartberg L, Nebeling B, Schmoldt A (2003) Mood, cognition and serotonin transporter availability in current and former ecstasy (MDMA) users. Psychopharmacology (Berl) 167:85–96Google Scholar
  44. Thomasius R, Zapletalova P, Petersen K, Buchert R, Andresen B, Wartberg L, Nebeling B, Schmoldt A (2006) Mood, cognition and serotonin transporter availability in current and former ecstasy (MDMA) users: the longitudinal perspective. J Psychopharmacol 20:211–225PubMedCrossRefGoogle Scholar
  45. Wechsler D (1987) Wechsler memory scale-revised: manual. Psychological, New York, NYGoogle Scholar
  46. Wilson AA, Ginovart N, Schmidt M, Meyer JH, Threlkeld PG, Houle S (2000) Novel radiotracers for imaging the serotonin transporter by positron emission tomography: synthesis, radiosynthesis, and in vitro and ex vivo evaluation of (11)C-labeled 2-(phenylthio)araalkylamines. J Med Chem 43:3103–3110PubMedCrossRefGoogle Scholar
  47. Yuan J, Cord BJ, McCann UD, Callahan BT, Ricaurte GA (2002) Effect of depleting vesicular and cytoplasmic dopamine on methylenedioxymethamphetamine neurotoxicity. J Neurochem 80:960–969PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Una D. McCann
    • 1
    • 4
  • Zsolt Szabo
    • 2
  • Melin Vranesic
    • 2
  • Michael Palermo
    • 3
  • William B. Mathews
    • 2
  • Hayden T. Ravert
    • 2
  • Robert F. Dannals
    • 2
  • George A. Ricaurte
    • 3
  1. 1.Department of PsychiatryThe Johns Hopkins School of MedicineBaltimoreUSA
  2. 2.Department of RadiologyThe Johns Hopkins School of MedicineBaltimoreUSA
  3. 3.Department of NeurologyThe Johns Hopkins School of MedicineBaltimoreUSA
  4. 4.Department of Psychiatry and Behavioral SciencesThe Johns Hopkins School of MedicineBaltimoreUSA

Personalised recommendations