Autophagy Inhibition Plays a Protective Role against 3, 4-Methylenedioxymethamphetamine (MDMA)-induced Loss of Serotonin Transporters and Depressive-like Behaviors in Rats

Publication date: Available online 28 February 2019Source: Pharmacological ResearchAuthor(s): Jui-Hu Shih, Chuang-Hsin Chiu, Kuo-Hsing Ma, Yuahn-Sieh Huang, Chyng-Yann Shiue, Ting-Yin Yeh, Li-Ting Kao, Yang-Yi Lin, I-Hsun LiAbstractThe 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...
Source: Pharmacological Research - Category: Drugs & Pharmacology Source Type: research