Preliminary Results on the Long-Term Effects of Dextromethorphan on MDMA-Mediated Serotonergic Deficiency and Volumetric Changes in Primates Based on 4-[18F]-ADAM PET/MRI

Frontiers in Neuroscience

Tsung-Hsun Yu¹  Kuo-Hsing Ma²  Chi-Jung Tsai⁴  Wen-Sheng Huang⁴  Cheng-Yi Cheng⁵  Chuang-Hsin Chiu⁵  Yu-Yeh Kuo⁶  Leo Garcia Flores II⁷  Skye Hsin-Hsien Yeh⁸ 

[1] Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan;Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan;Department of Nuclear Medicine, Cheng-Hsin General Hospital, Taipei, Taiwan;Department of Nuclear Medicine, Taipei Medical University Hospital, Taipei, Taiwan;Department of Nuclear Medicine, Tri-Service General Hospital, Taipei, Taiwan;Department of Nursing, Hsin-Sheng College of Medical Care and Management, Taoyuan, Taiwan;Radiomedix, Inc., Houston, TX, United States;School of Medicine, National Defense Medical Center, Taipei, Taiwan;

关键词: 4-[18F]-ADAM PET;    MDMA-induced serotonergic deficiency;    SERT reversibility;    volumetric changes;    neuroprotective effects of dextromethorphan;   

DOI  :  10.3389/fnins.2022.837194

来源: DOAJ

【 摘 要 】

Alterations to the serotonergic system due to 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) consumption have been extensively documented. However, knowledge of the reversibility of these neurotoxic effects based on in vivo evaluations of serotonin transport (SERT) availability remains limited. This study aimed to evaluate the long-term neurotoxicity of MDMA after 66 months abstinence and explored whether Dextromethorphan, a non-competitive N-methyl-D-aspartate (NMDA) receptor, could attenuate MDMA-induced neurotoxicity using 4-[18F]-ADAM, an imaging ligand that selectively targets SERT, with positron emission tomography technology (PET). Nine monkeys (Macaca cyclopis) were used in this study: control, MDMA, and DM + MDMA. Static 4-[18F]-ADAM PET was performed at 60 and 66 months after drug treatment. Serotonin transport (SERT) availability was presented as the specific uptake ratios (SURs) of 4-[18F]-ADAM in brain regions. Voxel-based region-specific SERT availability was calculated to generate 3D PET/MR images. Structural Magnetic Resonance Imaging (MRI) volumetric analysis was also conducted at 60 months. Significantly decreased 4-[18F]-ADAM SURs were observed in the striatum and thalamus of the MDMA group at 60 and 66 months compared to controls; the midbrain and frontal cortex SURs were similar at 60 and 66 months in the MDMA and control groups. All eleven brain regions showed significantly lower (∼13%) self-recovery rates over time; the occipital cortex and cingulate recovered to baseline by 66 months. DM attenuated MDMA-induced SERT deficiency on average, by ∼8 and ∼1% at 60 and 66 months, respectively; whereas significant differences were observed between the thalamus and amygdala of the MDMA and DM + MDMA groups at 66 months. Compared to controls, the MDMA group exhibited significantly increased (∼6.6%) gray matter volumes in the frontal cortex, occipital cortex, caudate nucleus, hippocampus, midbrain, and amygdala. Moreover, the gray matter volumes of the occipital cortex, hippocampus and amygdala correlated negatively with the 4-[18F]-ADAM SURs of the same regions. DM (n = 2) did not appear to affect MDMA-induced volumetric changes. The 4-[18F]-ADAM SURs, lower self-recovery rate and increased volumetric values indicate the occipital cortex, hippocampus and amygdala still exhibit MDMA-induced neurotoxicity after 66 months’ abstinence. Moreover, DM may prevent MDMA-induced serotonergic deficiency, as indicated by increased 4-[18F]-ADAM SURs and SERT availability, but not volumetric changes.

【 授权许可】

Unknown