Ecstasy-induced reduction of the availability of the brain serotonin transporter as revealed by [11C](+)McN5652-PET and the multi-linear reference tissue model: loss of transporters or artifact of tracer kinetic modelling?
Restricted accessOtherFirst published online August, 2007
Ecstasy-induced reduction of the availability of the brain serotonin transporter as revealed by [11C](+)McN5652-PET and the multi-linear reference tissue model: loss of transporters or artifact of tracer kinetic modelling?
In a previous positron emission tomography (PET) study with the serotonin transporter (SERT) ligand [11C](+)McN5652, we found protracted reduction of the availability of the brain SERT in users of the drug ecstasy. However, the multi-linear reference tissue method for the quantification of SERT availability used in this study is prone to effects of altered levels of statistical noise that c`ould simulate reduction of SERT. The aim of the present study was to take into account this confound by re-evaluation of the data now using a modelling approach that is rather insensitive to alterations in the level of statistical noise. A total of 116 subjects (30 current, 29 former ecstasy users, 29 drug-naive, 28 polydrug controls) in whom [ 11C](+)McN5652-PET had been performed previously were re-evaluated. The equilibrium specific-to-non-specific partition coefficient V" 3 was obtained voxel-wise by application of the simplified reference tissue method (SRTM), which provides quite unbiased results up to rather large noise levels. Voxel-based comparisons between the groups were performed using statistical parametric mapping. V"3 was reduced in the striatum and in the thalamus in current ecstasy users. This was confirmed by volume-of-interest-based analysis. This result suggests that the ecstasy-induced reduction of SERT availability in SERT-rich brain regions reported previously indicates reduced SERT binding potential rather than being an artifact of tracer kinetic modelling. SRTM analysis did not confirm previous findings in neocortical brain areas.
Acton P.D., Choi S.R., Hou C., Plossl K., Kung H.F. (2001) Quantification of serotonin transporters in nonhuman primates using [(123)I]ADAM and SPECT. J Nucl Med42: 1556—1562
2.
Armitage B., Berry G. (1994) Statistical Methods in Medical Research. Blackwell Science, Oxford
3.
Buchert R., Varga J., Mester J. (2004a) Limitations of bi-linear regression analysis for the determination of receptor occupancy with positron emission tomography . Nucl Med Commun25: 451—459
4.
Buchert R., Wilke F., van den Hoff J., Mester J. (2003a) Improved statistical power of the multilinear reference tissue approach to the quantification of neuroreceptor ligand binding by regularization. J Cereb Blood Flow Metab23: 612—620
5.
Buchert R., Thomasius R., Wilke F., Petersen K., Nebeling B., Obrocki J., Schulze O., Schmidt U., Clausen M. (2004b) A voxel-based investigation of long-term effects of `ecstasy' consumption on brain serotonin transporters using positron emission tomography. Am J Psychiatry161: 1181—1189
6.
Buchert R., Thomasius R., Nebeling B., Petersen K., Obrocki J., Jenicke L., Wilke F., Wartberg L., Zapletalova P., Clausen M. (2003b) Long-term effects of `ecstasy' use on serotonin transporters of the brain investigated by PET. J Nucl Med44: 375—384
7.
Buck A., Gucker P.M., Schonbachler R.D., Arigoni M., Kneifel S., Vollenweider F.X., Ametamey S.M., Burger C. (2000) Evaluation of serotonergic transporters using PET and [11C](+)McN-5652: assessment of methods. J Cereb Blood Flow Metab20: 253—262
8.
Carson R.E. (1993) PET parameter estimation using linear integration methods: bias and variability. In Uemura K, Lassen N. A, Jones T, Kanno I. Quantification of Brain Function: Tracer Kinetic and Image Analysis in Brain PET. Excerpta Medica, New York , pp. 499—507
9.
Chang L., Grob C.S., Ernst T., Itti L., Mishkin F.S., Jose-Melchor R., Poland R.E. (2000) Effect of ecstasy [3,4-methylenedioxymethamphetamine (MDMA)] on cerebral blood flow: a co-registered SPECT and MRI study. Psychiatry Res98: 15—28
10.
Crone C. (1963) The permeability of capillaries in various organs as determined by use of the `indicator diffusion' method. Acta Physiol Scand58: 292—305
11.
Cunningham V.J., Gunn R.N., Matthews J.C. (2004) Quantification in positron emission tomography for research in pharmacology and drug development. Nucl Med Commun25: 643—646
12.
Friston K.J., Holmes A.P., Worsley K.J., Poline J.P., Frith C.D., Frackowiak R S J (1995) Statistical parametric maps in functional imaging: a general linear approach. Human Brain Mapping2: 189—210
13.
Green A.R., Cross A.J., Goodwin G.M. (1995) Review of the pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA or `Ecstasy'). Psychopharmacology (Berl)119: 247—260
14.
Gunn R.N., Lammertsma A.A., Hume S.P., Cunningham V.J. (1997) Parametric imaging of ligand-receptor binding in PET using a simplified reference region model. Neuroimage6: 279—287
15.
Hesse S., Barthel H., Murai T., Muller U., Muller D., Seese A., Kluge R., Sabri O. (2003) Is correction for age necessary in neuroimaging studies of the central serotonin transporter? Eur J Nucl Med MolImaging30: 427—430
16.
Ichise M., Toyama H., Innis R.B., Carson R.E. (2002) Strategies to improve neuroreceptor parameter estimation by linear regression analysis. J Cereb Blood Flow Metab22: 1271—1281
17.
Ichise M., Ballinger J.R., Golan H., Vines D., Luong A., Tsai S., Kung H.F. (1996) Noninvasive quantification of dopamine D2 receptors with iodine-123-IBF SPECT. J Nucl Med37: 513—520
18.
Ichise M., Liow J.S., Lu J.Q., Takano A., Model K., Toyama H., Suhara T., Suzuki K., Innis R.B., Carson R.E. (2003) Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab23: 1096—1112
19.
Kish S.J., Furukawa Y., Chang L.J., Tong J., Ginovart N., Wilson A., Houle S., Meyer J.H. (2005) Regional distribution of serotonin transporter protein in postmortem human brain: is the cerebellum a SERT-free brain region?Nucl Med Biol32: 123—128
20.
Lammertsma A.A., Hume S.P. (1996) Simplified reference tissue model for PET receptor studies. Neuroimage4: 153—158
21.
Laruelle M., Vanisberg M-A., Maloteaux J-M. (1988) Regional and subcellular localization in human brain of [3H]paroxetine binding, a marker of serotonin uptake sites. Biol Psychiatry24: 299—309
22.
Laruelle M., Slifstein M., Huang Y. (2003) Relationships between radiotracer properties and image quality in molecular imaging of the brain with positron emission tomography . Mol Imaging Biol5: 363—375
23.
McCann U.D., Szabo Z., Seckin E., Rosenblatt P., Mathews W.B., Ravert H.T., Dannals R.F., Ricaurte G.A. (2005) Quantitative PET studies of the serotonin transporter in MDMA users and controls using [11C]McN5652 and [11C]DASB. Neuropsychopharmacology30: 1741—1750
24.
Meyer J.H., Ichise M. (2001) Modeling of receptor ligand data in PET and SPECT imaging: a review of major approaches. J Neuroimaging11: 30—39
25.
Mintun M.A., Raichle M.E., Kilbourn M.R., Wooten G.F., Welch M.J. (1984) A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol15: 217—227
26.
Parrott A.C. (1998) The psychobiology of MDMA or `ecstasy': symposium arranged by the Psychobiology Section, at the Annual Conference of the British Psychological Society, Heriot-Watt University , Edinburgh, April 1997. J Psychopharmacol 12: 97—102
27.
Parrott A.C. (2004) Is ecstasy MDMA? A review of the proportion of ecstasy tablets containing MDMA, their dosage levels, and the changing perceptions of purity. Psychopharmacology (Berl)173: 234—241
28.
Parrott A.C., Gouzoulis-Meyfrank E., Rodgers J., Solowij N. (2004) Ecstasy/MDMA and cannabis: the complexities of their interactive neuropsychobiological effects. J Psychopharmacol18: 572—575
29.
Parsey R.V., Kegeles L.S., Hwang D.R., Simpson N., Abi-Dargham A., Mawlawi O., Slifstein M., Van Heertum R.L., Mann J.J., Laruelle M. (2000) In vivo quantification of brain serotonin transporters in humans using [11C]McN5652. J Nucl Med41: 1465—1477
30.
Press W.H., Teukolsky S.A., Vetterling W.T., Flannery B.P. (2002). Numerical Recipes in C: The Art of Scientific Computing. Cambridge University Press, Cambridge
31.
Reneman L., Lavalaye J., Schmand B., de Wolff F.A., van den Brink W., den Heeten G.J., Booij J. (2001a) Cortical serotonin transporter density and verbal memory in individuals who stopped using 3,4-methylenedioxymethamphetamine (MDMA or `ecstasy'): preliminary findings. Arch Gen Psychiatry58: 901—906.
32.
Reneman L., Booij J., de Bruin K., Reitsma J.B., de Wolff F.A., Gunning W.B., den Heeten G.J., van den Brink W. (2001b) Effects of dose, sex, and long-term abstention from use on toxic effects of MDMA (ecstasy) on brain serotonin neurons. Lancet358: 1864—1869.
33.
Renkin E.M. (1959) Transport of potassium-42 from blood to tissue in isolated mammalian skeletal muscles. Am J Physiol197: 1205—1210
34.
Slifstein M., Laruelle M. (2000) Effects of statistical noise on graphic analysis of PET neuroreceptor studies. J Nucl Med41: 2083—2088
35.
Smidt G. (2004) Bewegungsartefakte bei PET-Hirn-Rezeptor-Studien . Department of Nuclear Medicine. Hamburg, University Medical CenterHamburg-Eppendorf, p. 37
36.
Stamatakis E.A., Glabus M.F., Wyper D.J., Barnes A., Wilson J.T. (1999) Validation of statistical parametric mapping (SPM) in assessing cerebral lesions: a simulation study. Neuroimage10: 397—407
37.
Szabo Z., Scheffel U., Mathews W.B., Ravert H.T., Szabo K., Kraut M., Palmon S., Ricaurte G.A., Dannals R.F. (1999) Kinetic analysis of C-11 McN5652: a serotonin transporter radioligand. J Cereb Blood Flow Metab19: 967—981
38.
Thiele F., Mollus S., Spies L., Thomasius R., Buchert R. (2005) Investigation of ecstasy-induced changes of serotonin transporter availability: statistical power of nonlinear versus linear regression . Society of Nuclear Medicine, 52nd Annual Meeting , Toronto
39.
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—96
40.
Tzourio-Mazoyer N., Landeau B., Papathanassiou D., Crivello F., Etard O., Delcroix N., Mazoyer B., Joliot M. (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage15: 273—289
41.
Verheyden S.L., Maidment R., Curran H.V. (2003) Quitting ecstasy: an investigation of why people stop taking the drug and their subsequent mental health. J Psychopharmacol17: 371—378
42.
Wager T.D., Keller M.C., Lacey S.C., Jonides J. (2005) Increased sensitivity in neuroimaging analyses using robust regression. Neuroimage26: 99—113
43.
Wu Y., Carson R.E. (2002) Noise reduction in the simplified reference tissue model for neuroreceptor functional imaging. J Cereb Blood Flow Metab22: 1440—1452
