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

Kuo-Hsing Ma,Chien-Fu F Chen,Yuahn-Sieh Huang,Mei-Hsiu Liao,Cheng-Yi Cheng,Wen-Sheng Huang,Tsung-Ta Liu,Shao-Ju Weng,Chi-Chang Sung,Te-Hung Hsu,Kang-Wei Chang,Sheau-Huei Chueh

doi:10.1038/srep38695

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.

Highlights

3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a ring-substituted amphetamine derivative
We demonstrated that MDMA induced long-term serotonergic lesions in the brain of macaques on [123I]-ADAM/single photon emission computerized tomography (SPECT) scan
We showed that co-treatment with DM abolished MDMA-induced aberration in serotonin transporters (SERT) density in several brain regions of the non-human primate

Summary

Introduction

3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a ring-substituted amphetamine derivative It has attracted a great deal of media attention in the recent years due to its widespread abuse as a recreational drug by young people[1]. DM is known for its acceptable safety and efficacy profiles with no sedative or addictive properties at recommended antitussive doses[18,19] It is a relatively selective and specific NMDA receptor antagonist and reported to inhibit serotonin uptake into neurons[20,21,22,23]. Dynamic imaging of SPECT was performed to evaluate protective effects of DM against MDMA-induced damage in the serotonergic system, which is associated with density of SERT of the monkey brains

Methods

Results

Conclusion