Involvement of autophagy upregulation in 3,4-methylenedioxymethamphetamine ('ecstasy')-induced serotonergic neurotoxicity.
I-Hsun Li, Kuo-Hsing Ma, Tzu-Jen Kao, Yang-Yi Lin, Shao-Ju Weng, Ting-Yin Yen, Lih-Chi Chen, Yuahn-Sieh Huang
Neurotoxicology January 2016 DOI: 10.1016/j.neuro.2015.11.009 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro and in vivo animal study Peer reviewed |
|---|---|
| Population | Cultured rat serotonergic neurons and an in vivo animal model |
| Interventions | MDMA 3-methyladenine (3-MA) rapamycin bafilomycin A1 |
| Measures | LC3B staining, neurite outgrowth, animal-PET with 4-[(18)F]-ADAM |
| Topics | MDMA Serotonin |
| Keywords | 3-methyladenine Autophagy Lc3b Serotonergic neuron Tryptophan hydroxylase |
| Key points | MDMA exposure induced LC3B-densely stained autophagosome formation and decreased neurite outgrowth in cultured rat serotonergic neurons. Blocking autophagy with 3-methyladenine reduced autophagosome accumulation and lessened MDMA-triggered neurite damage and neuron death, whereas enhancing autophagy flux with rapamycin or impairing autophagosome clearance with bafilomycin A1 aggravated neurite degeneration. In MDMA-treated animals, 3-methyladenine protected against MDMA-induced downregulation of SERT measured by animal-PET with 4-[(18)F]-ADAM, suggesting MDMA-triggered autophagy is detrimental to serotonergic neurons. |
Abstract
It has been suggested that autophagy plays pathogenetic roles in cerebral ischemia, brain trauma, and neurodegenerative disorders. 3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is an illicit drug that causes long-term serotonergic neurotoxicity in the brain. Apoptosis and necrosis have been implicated in MDMA-induced neurotoxicity, but the role of autophagy in MDMA-elicited serotonergic toxicity has not been investigated. The present study aimed to examine the contribution of autophagy to neurotoxicity in serotonergic neurons in in vitro and in vivo animal models challenged with MDMA. Here, we demonstrated that in cultured rat serotonergic neurons, MDMA exposure induced LC3B-densely stained autophagosome formation, accompanying by a decrease in neurite outgrowth. Autophagy inhibitor 3-methyladenine (3-MA) significantly attenuated MDMA-induced autophagosome accumulation, and ameliorated MDMA-triggered serotonergic neurite damage and neuron death. In contrast, enhanced autophagy flux by rapamycin or impaired autophagosome clearance by bafilomycin A1 led to more autophagosome accumulation in serotonergic neurons and aggravated neurite degeneration. In addition, MDMA-induced autophagy activation in cultured serotonergic neurons might be mediated by serotonin transporter (SERT). In an in vivo animal model administered MDMA, neuroimaging showed that 3-MA protected the serotonin system against MDMA-induced downregulation of SERT evaluated by animal-PET with 4-[(18)F]-ADAM, a SERT radioligand. Taken together, our results demonstrated that MDMA triggers upregulation of autophagy in serotonergic neurons, which appears to be detrimental to neuronal growth.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 5
- MDMA (3,4-methylenedioxy-methamphetamine) Drug Addiction Mechanisms in the Brain April 8, 2024
- Lysosomal Dysfunction and Autophagy Blockade Contribute to MDMA-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells. Chemical Research in Toxicology April 20, 2020
- Autophagy inhibition plays a protective role against 3, 4‐methylenedioxymethamphetamine (MDMA)‐induced loss of serotonin transporters and depressive‐like behaviors in rats Pharmacological Research February 28, 2019
- MDMA-induced neurotoxicity of serotonin neurons involves autophagy and rilmenidine is protective against its pathobiology. Neurochemistry International May 2017
- Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT. Scientific Reports December 12, 2016
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and 12 more in the library