title: Critical role of peripheral vasoconstriction in fatal brain hyperthermia induced by MDMA (Ecstasy) under conditions that mimic human drug use.
abstract: MDMA (Ecstasy) is an illicit drug used by young adults at hot, crowed "rave" parties, yet the data on potential health hazards of its abuse remain controversial. Here, we examined the effect of MDMA on temperature homeostasis in male rats under standard laboratory conditions and under conditions that simulate drug use in humans. We chronically implanted thermocouple microsensors in the nucleus accumbens (a brain reward area), temporal muscle, and facial skin to measure temperature continuously from freely moving rats. While focusing on brain hyperthermia, temperature monitoring from the two peripheral locations allowed us to evaluate the physiological mechanisms (i.e., intracerebral heat production and heat loss via skin surfaces) that underlie MDMA-induced brain temperature responses. Our data confirm previous reports on high individual variability and relatively weak brain hyperthermic effects of MDMA under standard control conditions (quiet rest, 22-23°C), but demonstrate dramatic enhancements of drug-induced brain hyperthermia during social interaction (exposure to male conspecific) and in warm environments (29°C). Importantly, we identified peripheral vasoconstriction as a critical mechanism underlying the activity- and state-dependent potentiation of MDMA-induced brain hyperthermia. Through this mechanism, which prevents proper heat dissipation to the external environment, MDMA at a moderate nontoxic dose (9 mg/kg or ~1/5 of LD50 in rats) can cause fatal hyperthermia under environmental conditions commonly encountered by humans. Our results demonstrate that doses of MDMA that are nontoxic under cool, quiet conditions can become highly dangerous under conditions that mimic recreational use of MDMA at rave parties or other hot, crowded venues.
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse-National Institutes of Health, Baltimore, Maryland 21224 ekiyatki@intra.nida.nih.gov.
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Kiyatkin
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse-National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Albert H
authors.initials: AH
authors.lastname: Kim
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse-National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Ken T
authors.initials: KT
authors.lastname: Wakabayashi
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse-National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse-National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Yavin
authors.initials: Y
authors.lastname: Shaham
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000139:chemically induced* / Q000401:mortality / Q000473:pathology*; D006213:Hallucinogens / Q000633:toxicity*; D007398:Interpersonal Relations; D008124:Locomotion / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009714:Nucleus Accumbens / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D012867:Skin / Q000187:drug effects / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D006213:Hallucinogens; D018817:N-Methyl-3,4-methylenedioxyamphetamine
keywords: MDMA; acute intoxication; brain temperature; peripheral vasoconstriction; social interaction; warm environment