In vivo detection of short- and long-term MDMA neurotoxicity--a positron emission tomography study in the living baboon brain.
The present study evaluated short- and long-term effects of MDMA (3,4-methylenedioxymethamphetamine) in the baboon brain using PET and [11C](+)McN 5652, a potent 5-HT transporter ligand, as well as [11C]RTI-55, a cocaine derivative which labels both 5-HT and dopamine transporters. Following baseline PET scans with [11C](+)McN5652, [11C](-)McN5652 (the inactive enantiomer of the active enantiomer [11C](+)McN5652) and [11C]RTI-55, a baboon was treated with MDMA (5 mg/kg, s.c., twice daily for four consecutive days). PET studies at 13, 19, and 40 days post-MDMA revealed decreases in mean radioactivity levels in all brain regions when using [11C](+)McN 5652, but not with [11C](-)McN5652 or [11C]RTI-55. Reductions in specific [11C](+)McN5652 binding (calculated as the difference in radioactivity concentrations between (+) and (-)[11C]McN5652) ranged from 44% in the pons to 89% in the occipital cortex. PET studies at 9 and 13 months showed regional differences in the apparent recovery of 5-HT transporters, with increases in some brain regions (e.g., hypothalamus) and persistent decreases in others (e.g., neocortex). Data obtained from PET studies correlated well with regional 5-HT axonal marker concentrations in the CNS measured after sacrifice of the animal. The results of these studies indicate that PET imaging of the living nonhuman primate brain with [11C](+)McN5652 can detect changes in regional 5-HT transporter density secondary to MDMA-induced neurotoxicity. Using PET, it should also be feasible to use [11C](+)McN5652 to determine whether human MDMA users are also susceptible to MDMA's neurotoxic effects.
Scheffel
U
U
Department of Radiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
Szabo
Z
Z
Mathews
W B
WB
Finley
P A
PA
Dannals
R F
RF
Ravert
H T
HT
Szabo
K
K
Yuan
J
J
Ricaurte
G A
GA
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging*; D001923:Brain Chemistry / Q000187:drug effects; D001927:Brain Diseases / Q000139:chemically induced* / Q000000981:diagnostic imaging*; D002247:Carbon Isotopes; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives; D007457:Iodine Radioisotopes; D007546:Isoquinolines; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009419:Nerve Tissue Proteins; D010215:Papio; D011869:Radioligand Assay; D018490:Serotonin Agents / Q000633:toxicity*; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D014055:Tomography, Emission-Computed
D002247:Carbon Isotopes; D002352:Carrier Proteins; D007457:Iodine Radioisotopes; D007546:Isoquinolines; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; C058079:McN 5652; D003042:Cocaine; D018817:N-Methyl-3,4-methylenedioxyamphetamine