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Antagonists for serotonin receptors ameliorate rhabdomyolysis induced by 25D-NBOMe, a psychoactive designer drug

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Abstract

Purpose

N-Benzyl-substituted phenethylamines (NBOMes) are psychoactive drugs, which induce various symptoms like serotonin syndrome, even at low doses. Recently, we reported the first lethal case of a designer drug, 2-(4-bromo-2, 5-dimethoxyphenyl)-NBOMe (25B-NBOMe) intoxication with severe rhabdomyolysis, evaluated by clinical, pathological, and toxicological analyses. We also confirmed that 25B-NBOMe can induce rhabdomyolysis using a zebrafish model. To further elucidate pathomechanism of NBOMes-induced rhabdomyolysis, we treated zebrafish with a similar designer drug, 2-(4-methyl-2, 5-dimethoxyphenyl)-NBOMe (25D-NBOMe).

Methods

Zebrafish treated with a designer drug, 25D-NBOMe, were examined survival rate and were analyzed skeletal muscle degeneration by birefringence. They were also analyzed expression levels of 5-HT2A and 5-HT2C receptors and ryanodine receptor.

Results

The 25D-NBOMe-treated fish showed decreased survival rate and skeletal muscle degeneration detected by birefringence mimicking to those of 25B-NBOMe-treated fish. We revealed that 25D-NBOMe induced up-regulation of the expression of 5-HT2A and 5-HT2C receptors, and rhabdomyolysis was inhibited by the 5-HT2A receptor antagonist, aripiprazole and 5-HT2C receptor antagonist, SB242084. Moreover, ryanodine receptor expression was up-regulated in 25D-NBOMe-treated fish as compared to that of untreated fish, and the up-regulated expression of ryanodine receptor in 25D-NBOMe-treated fish was improved with co-treatment aripiprazole and SB242084.

Conclusions

Our findings suggest that multiple 5-HT receptors have important roles in NBOMes-induced rhabdomyolysis together with other serotonin-related symptoms. Zebrafish is a highly useful model for therapeutic studies of rhabdomyolysis induced by psychoactive designer drugs.

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Acknowledgements

This work was supported partly by a Grant-in-Aid for Challenging Exploratory Research, Scientific Research (S) (B) and (C) from the Japan Society for the Promotion of Science (Grant nos. 18K19703, 16K09218, 17H06112, 16H05274), by the MEXT-Supported Program for the Strategic Research Foundation at Private Universities (Grant no. 5020-03), by Research on Rare and Intractable Diseases, Health and Labor Science Research (Grant no. H26-nanchitou(nan)-ippan-079), and by Intramural Research Grant for Neurological and Psychiatric Disorders of the National Center of Neurology and Psychiatry (29-4).

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Authors and Affiliations

  1. Department of Pathophysiology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan

    Genri Kawahara, Mami S. Nakayashiki & Yukiko K. Hayashi

  2. Department of Forensic Medicine, Tokyo Medical University, Tokyo, Japan

    Hideyuki Maeda & Ken-ichi Yoshida

  3. Division of Pharmacognosy, Phytochemistry and Narcotics, National Institute of Health Sciences, Kanagawa, Japan

    Ruri Kikura-Hanajiri

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  1. Genri Kawahara
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Correspondence to Yukiko K. Hayashi.

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Ethical approval

The use of zebrafish for this study was approved by the Experimental Animal Committee of Tokyo Medical University (approval number: H290067). This article does not contain any studies with human participants performed by any of the authors.

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Kawahara, G., Nakayashiki, M.S., Maeda, H. et al. Antagonists for serotonin receptors ameliorate rhabdomyolysis induced by 25D-NBOMe, a psychoactive designer drug. Forensic Toxicol 38, 122–128 (2020). https://doi.org/10.1007/s11419-019-00495-w

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