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.
Highlights
Club drugs, or “rave” drugs, are a class of recreational drugs associated with the location of usage, such as nightclubs, raves, and dance parties
We discovered that following hyperthermia there was increased secretion of Gaussia luciferase (GLuc)-ASARTDL whereas there was no change in GLuc-Untagged secretion (Figure 1a,b)
Cell culture plates were randomly chosen for hyperthermia versus normal temperature exposure, but the investigator was not blinded to the treatments
Summary
“rave” drugs, are a class of recreational drugs associated with the location of usage, such as nightclubs, raves, and dance parties. In these environments, the combination of a warm atmosphere, overcrowding, and dancing can contribute to elevated body temperature, or hyperthermia, which can negatively impact the body’s reaction to substances of abuse. MDMA is associated with drug-induced hyperthermia and consumption of the drug can itself cause hyperthermia in humans [3,4,5,6]. The potentiation of MDMA-induced hyperthermia by social interaction and warm ambient temperature has been recreated in rodent models [7]. The interplay between increased ambient temperature, drug usage, and cellular proteostasis has not been well documented
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