Caffeine and MDMA (Ecstasy) Exacerbate ER Stress Triggered by Hyperthermia

Abstract

Drugs of abuse can cause local and systemic hyperthermia, a known trigger of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Another trigger of ER stress and UPR is ER calcium depletion, which causes ER exodosis, the secretion of ER-resident proteins. In rodent models, club drugs such as 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) can create hyperthermic conditions in the brain and cause toxicity that is affected by the environmental temperature and the presence of other drugs, such as caffeine. In human studies, MDMA stimulated an acute, dose-dependent increase in core body temperature, but an examination of caffeine and MDMA in combination remains a topic for clinical research. Here we examine the secretion of ER-resident proteins and activation of the UPR under combined exposure to MDMA and caffeine in a cellular model of hyperthermia. We show that hyperthermia triggers the secretion of normally ER-resident proteins, and that this aberrant protein secretion is potentiated by the presence of MDMA, caffeine, or a combination of the two drugs. Hyperthermia activates the UPR but the addition of MDMA or caffeine does not alter the canonical UPR gene expression despite the drug effects on ER exodosis of UPR-related proteins. One exception was increased BiP/GRP78 mRNA levels in MDMA-treated cells exposed to hyperthermia. These findings suggest that club drug use under hyperthermic conditions exacerbates disruption of ER proteostasis, contributing to cellular toxicity.

Excitotoxic glutamate levels cause the secretion of resident endoplasmic reticulum proteins

“…ERS tails of proteins that move from ER to Golgi interact with KDEL receptors located in the Golgi and cause retrograde transport of the ERS-containing proteins from the Golgi back to the ER. We have previously shown that augmenting KDELR expression can attenuate exodosis caused by thapsigargin, hypoxia and hyperthermia 13,33 . We first investigated the ability of KDELR to influence Tg-induced GLuc-SERCaMP secretion in rat primary neurons transduced with AAV vectors expressing GLuc-SERCaMP and eYFP (control), KDELR1, or KDELR2.…”