Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT

Abstract

3,4-Methylenedioxymethamphetamine (MDMA), a common recreational drug, is known to cause serotonergic neurotoxicity in the brain. Dextromethorphan (DM) is a widely used antitussive reported to exert anti-inflammatory effect in vivo. In this study, we examined the long-term effect of MDMA on the primate serotonergic system and the protective property of DM against MDMA-induced serotonergic abnormality using single photon emission computed tomography (SPECT). Nine monkeys (Macaca cyclopis) were divided into three groups, namely control, MDMA and co-treatment (MDMA/DM). [123I]-ADAM was used as the radioligand for serotonin transporters (SERT) in SPECT scans. SERT levels of the brain were evaluated and presented as the uptake ratios (URs) of [123I]-ADAM in several regions of interest of the brain including midbrain, thalamus and striatum. We found that the URs of [123I]-ADAM were significantly lower in the brains of MDMA than control group, indicating lower brain SERT levels in the MDMA-treated monkeys. This MDMA-induced decrease in brain SERT levels could persist for over four years. However, the loss of brain SERT levels was not observed in co-treatment group. These results suggest that DM may exert a protective effect against MDMA-induced serotonergic toxicity in the brains of the non-human primate.

Amitriptyline Accelerates SERT Binding Recovery Rate in MDMA-Induced Rat Model: In Vivo 4-[18F]-ADAM PET Imaging

“…Using a selective SERT PET radiotracer, we monitored a long-term SERT occupancy/recovery in vivo and evaluated the AMI neuroprotection after MDMA induction. Our results showed that acute and repeated administration of MDMA signi cantly induced SERT reduction levels in all regions at day 14 compared to the controls, which were supported by previous studies, revealing that the effect of MDMA on SERT binding was a robust nding in rodents [13,20,42,43,44]. Those reports indicate that the effect of MDMA on SERT binding is a robust nding in rodent.…”

“…However, it decreased in cortical regions [49]. Ma et al, (2016) reported that the SERT recovery rate was on average of ~ 66.6% and ~ 68.6% after MDMA administration in the striatum, thalamus, and midbrain at 24 and 54 months, respectively [13].…”

“…Many studies have con rmed that MDMA can cause selective damage to rodents and primate's serotonin systems. In addition, MDMA has been demonstrated to reduce serotonin levels, serotonin reuptake transporter (SERT), and the amount of serotonin synthesis tryptophan hydroxylase important to enzymes in the use of MDMA after have signi cantly reduced [10,11,12,13]. These phenomena occur because of MDMA effect on serotonin neurons injury and MDMA inhibition of the presynaptic neuron into the tryptophan hydroxylase enzyme and the disintegration of monoamine oxidase-B (MAO-B).…”

“…The results showed a signi cant reduction in all brain regions of serotonin transporter [16,17]. By administering 5mg/kg MDMA subcutaneously twice daily for four consecutive days, the MDMA-induced decrease in brain SERT levels, which could persist for over four years in primates [13].…”

MDMA and the Brain: A Short Review on the Role of Neurotransmitters in the Cause of Neurotoxicity

“…In addition, the potential treatments to protect toxicity caused by MDMA have also been studied. Dextromethorphan and its metabolite, dextrorphan, may have a protective effect against MDMA-induced serotonergic toxicity in the brain (Finnegan, Skratt, Irwin, & Langston, 1989;Ma et al, 2016). Dextrorphan was believed to prevent the effects of serotonin depletion by MDMA in the striatum, hippocampus, and cortex (Finnegan et al, 1989).…”