Autophagy inhibition plays a protective role against 3, 4‐methylenedioxymethamphetamine (MDMA)‐induced loss of serotonin transporters and depressive‐like behaviors in rats
Jui-Hu Shih, Chuang-Hsin Chiu, Kuo-Hsing Ma, Y. Huang, C. Shiue, Ting-Yin Yeh, L. Kao, Yang-Yi Lin, I-Hsun Li
Pharmacological Research February 28, 2019 DOI: 10.1016/j.phrs.2019.02.026 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled animal (rat) experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Intervention | MDMA |
| Dose | MDMA 10 mg/kg s.c. twice daily; 3-MA 15 mg/kg i.p. |
| Duration | MDMA administered for 4 consecutive days; long-term SERT effects assessed by PET imaging (timing not specified) |
| Measures | Immunofluorescent staining for tryptophan hydroxylase and microtubule-associated protein 1 light chain 3 beta, immunohistochemical staining and positron emission tomography (PET) imaging for SERT density, plasma corticosterone measurements, forced swim tests |
| Topics | MDMA Serotonin |
| Key findings | Repeated MDMA increased autophagosome expression and reduced SERT density in rat striatum and frontal cortex; the autophagy inhibitor 3-MA lessened these reductions and was associated with lower forced-swim immobility and plasma corticosterone. The authors propose that autophagy inhibition may protect against MDMA-induced neurobiological and behavioral changes. |
Abstract
Graphical abstract Figure. No Caption available. Abstract The 3,4‐methylenedioxymethamphetamine (MDMA) is a popular recreational drug, which ultimately leads to serotonergic (5‐HT) neurotoxicity and psychiatric disorders. Previous in vitro studies have consistently demonstrated that MDMA provokes autophagic activation, as well as damage of 5‐HT axons and nerve fibers. So far, whether autophagy, a well‐conserved cellular process that is critical for cell fate, also participates in MDMA‐induced neurotoxicity in vivo remains elusive. Here, we first examined time‐course of autophagy‐related changes during repeated administration of MDMA (10 mg/kg s.c. twice daily for 4 consecutive days) using immunofluorescent staining for tryptophan hydroxylase and microtubule‐associated protein 1 light chain 3 beta in rats. We also evaluated the protective effects of 3‐methyadanine (3‐MA, an autophagy inhibitor, 15 mg/kg i.p.) against MDMA‐induced acute and long‐term reductions in serotonin transporters (SERT) density in various brain regions using immunohistochemical staining and positron emission tomography (PET) imaging respectively. Plasma corticosterone measurements and forced swim tests were performed to evaluate the depressive performance. The staining results showed that repeated administration of MDMA increased expression of autophagosome and caused reduction in SERT densities of striatum and frontal cortex, which was ameliorated in the presence of 3‐MA. PET imaging data also revealed that 3‐MA could ameliorate MDMA‐induced long‐term decreased SERT availability in various brain regions of rats. Furthermore, immobility time of forced swim tests and plasma corticosterone levels were less in the group of MDMA co‐injected with 3‐MA compared with that of MDMA group. Together, these findings suggest that autophagy inhibition may confer protection against neurobiological and behavioral changes induced by MDMA.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 4
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- Therapeutic effects of methimazole on 3,4-methylenedioxymethamphetamine-induced hyperthermia and serotonergic neurotoxicity. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie August 1, 2023
- Amitriptyline Accelerates SERT Binding Recovery in a Rat 3,4-Methylenedioxymethamphetamine (MDMA) Model: In Vivo 4-[18F]-ADAM PET Imaging International Journal of Molecular Sciences June 24, 2022
- MDMA and memory, addiction, and depression: dose-effect analysis Psychopharmacology March 1, 2022
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