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](+)McN 5652 can detect changes in regional 5-HT transporter density secondary to MI)MA-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.