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Numerous studies have confirmed that 3,4-Methylenedioxymethamphetamine (MDMA) produces long-lasting changes to the density of the serotonin reuptake transporter (SERT). Amitriptyline (AMI) has been shown to exert neuroprotective properties in neuropathologic injury. Here, we used a SERT-specific radionuclide, 4-[

Numerous studies have confirmed that 3,4-Methylenedioxymethamphetamine (MDMA) produces long-lasting changes to the density of the serotonin reuptake transporter (SERT). Amitriptyline (AMI) has been shown to exert neuroprotective properties in neuropathologic injury. Here, we used a SERT-specific radionuclide, 4-[18F]-ADAM, to assess the longitudinal alterations in SERT binding and evaluate the synergistic neuroprotective effect of AMI in a rat MDMA model. In response to MDMA treatment regimens, SERT binding was significantly reduced in rat brains. Region-specific recovery rate (normalized to baseline) in the MDMA group at day 14 was 71.29% ± 3.21%, and progressively increased to 90.90% ± 7.63% at day 35. AMI dramatically increased SERT binding in all brain regions, enhancing average ~18% recovery rate at day 14 when compared with the MDMA group. The immunochemical staining revealed that AMI markedly increased the serotonergic fiber density in the cingulate and thalamus after MDMA-induction, and confirmed the PET findings. Using in vivo longitudinal PET imaging, we demonstrated that SERT recovery was positively correlated with the duration of MDMA abstinence, implying that lower SERT densities in MDMA-induced rats reflected neurotoxic effects and were (varied) region-specific and reversible. AMI globally accelerated the recovery rate of SERT binding and increased SERT fiber density with possible neuroprotective effects.