The neurotoxicity of psychoactive phenethylamines “2C series” in cultured monoaminergic neuronal cell lines

Abstract

Purpose

The aim of this study was to evaluate the neurotoxicity of psychoactive abused 2,5-dimethoxy-substituted phenethylamines “2C series” in monoaminergic neurons.

Methods

After the exposure to “2C series”, 2,5-dimethoxy-4-propylthiophenethylamine (2C-T-7), 2,5-dimethoxy-4-isopropylthiophenethylamine (2C-T-4), 2,5-dimethoxy-4-ethylthiophenthylamine (2C-T-2), 2,5-dimethoxy-4-iodophenethylamine (2C-I) or 2,5-dimethoxy-4-chlorophenethylamine (2C-C), we examined their neurotoxicity, morphological changes, and effects of concomitant exposure to 3,4-methylenedioxymethamphetamine (MDMA) or methamphetamine (METH), using cultured neuronal dopaminergic CATH.a cells and serotonin-containing B65 cells.

Results

Single dose exposure to “2C series” for 24 h showed significant cytotoxicity as increase in lactate dehydrogenase (LDH) release from both monoaminergic neurons: 2C-T-7, 2C-C (EC50; 100 µM) > 2C-T-2 (150 µM), 2C-T-4 (200 µM) > 2C-I (250 µM) in CATH.a cells and 2C-T-7, 2C-I (150 µM) > 2C-T-2 (250 µM) > 2C-C, 2C-T-4 (300 µM) in B65 cells. The “2C series”-induced neurotoxicity in both cells was higher than that of MDMA or METH (EC50: ≥ 1–2 mM). In addition, apoptotic morphological changes were observed at relatively lower concentrations of “2C series”. The concomitant exposure to non-toxic dose of MDMA or METH synergistically enhanced 2C series drugs-induced LDH release and apoptotic changes in B65 cells, but to a lesser extent in CATH.a cells. In addition, the lower dose of 2C-T-7, 2C-T-2 or 2C-I promoted reactive oxygen species production in the mitochondria of B65 cells, even at the early stages (3 h) without apparent morphological changes.

Conclusion

The 2,5-dimethoxy-substitution of “2C series” induced severe neurotoxicity in both dopaminergic and serotonin-containing neurons. The non-toxic dose of MDMA or METH synergistically enhanced its neurotoxicity in serotonergic neurons.

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Acknowledgements

This work was supported by Health and Labour Sciences Research Grants for Research on Regulatory Science of Pharmaceuticals and Medical Devices (to M.A., M.F.) from the Japanese Ministry of Health, Labour and Welfare, and by a Research Grant from the Okayama Medical Foundation (to I.M.).

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Correspondence to Masato Asanuma.

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Asanuma, M., Miyazaki, I. & Funada, M. The neurotoxicity of psychoactive phenethylamines “2C series” in cultured monoaminergic neuronal cell lines. Forensic Toxicol 38, 394–408 (2020). https://doi.org/10.1007/s11419-020-00527-w

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Keywords

  • Psychoactive drugs
  • 2,5-Dimethoxy-substituted phenethylamines
  • Neurotoxicity
  • Serotonin-containing neurons
  • Dopamine neurons
  • Reactive oxygen species