IN-VIVO DETECTION OF SHORT-TERM 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-m ethylenedioxymethamphetamine) in the baboon brain using PET and [C-11] (+)McN5652, a potent 5-HT transporter ligand, as well as [C-11]RTI-55, a cocaine derivative which labels both 5-HT and dopamine transporters . Following baseline PET scans with [C-11](+)McN5652, [C-11](-)McN5652 (the inactive enantiomer of the active enantiomer [C-11](+)McN5652) a nd [C-11]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 p ost-MDMA revealed decreases in mean radioactivity levels in all brain regions when using [C-11](+)McN5652, but not with [C-11](-)McN5652 or [C-11]RTI-55. Reductions in specific [C-11](+)McN5652 binding (calcula ted as the difference in radioactivity concentrations between (+) and (-)[C-11]McN5652) ranged from 44% in the pens 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 bra in regions (e.g., hypothalamus) and persistent decreases in others (e. g., neocortex). Data obtained from PET studies correlated well with re gional 5-HT axonal marker concentrations in the CNS measured after sac rifice of the animal. The results of these studies indicate that PET i maging of the living nonhuman primate brain with [C-11](+)McN5652 can detect changes in regional 5-HT transporter density secondary to MDMA- induced neurotoxicity. Using PET, it should also be feasible to use [C -11](+)McN5652 to determine whether human MDMA users are also suscepti ble to MDMA's neurotoxic effects. (C) 1998 Wiley-Liss, Inc.