The relationship between core body temperature and 3,4-methylenedioxymethamphetamine metabolism in rats: implications for neurotoxicity.
BACKGROUND
A close relationship appears to exist between 3,4-methylenedioxymethamphetamine (MDMA)-induced changes in core body temperature and long-term serotonin (5-HT) loss.


OBJECTIVE
We investigated whether changes in core body temperature affect MDMA metabolism.


METHODS
Male Wistar rats were treated with MDMA at ambient temperatures of 15, 21.5, or 30 degrees C to prevent or exacerbate MDMA-induced hyperthermia. Plasma concentrations of MDMA and its main metabolites were determined for 6 h. Seven days later, animals were killed and brain indole content was measured.


RESULTS
The administration of MDMA at 15 degrees C blocked the hyperthermic response and long-term 5-HT depletion found in rats treated at 21.5 degrees C. At 15 degrees C, plasma concentrations of MDMA were significantly increased, whereas those of three of its main metabolites were reduced when compared to rats treated at 21.5 degrees C. By contrast, hyperthermia and indole deficits were exacerbated in rats treated at 30 degrees C. Noteworthy, plasma concentrations of MDMA metabolites were greatly enhanced in these animals. Instrastriatal perfusion of MDMA (100 microM for 5 h at 21 degrees C) did not potentiate the long-term depletion of 5-HT after systemic MDMA. Furthermore, interfering in MDMA metabolism using the catechol-O-methyltransferase inhibitor entacapone potentiated the neurotoxicity of MDMA, indicating that metabolites that are substrates for this enzyme may contribute to neurotoxicity.


CONCLUSIONS
This is the first report showing a direct relationship between core body temperature and MDMA metabolism. This finding has implications on both the temperature dependence of the mechanism of MDMA neurotoxicity and human use, as hyperthermia is often associated with MDMA use in humans.
Goni-Allo
Beatriz
B
Department of Pharmacology, School of Medicine, University of Navarra, c/ Irunlarrea 1, 31008 Pamplona, Spain.
O Mathúna
Brian
B
Segura
Mireia
M
Puerta
Elena
E
Lasheras
Berta
B
de la Torre
Rafael
R
Aguirre
Norberto
N
D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology*; D001923:Brain Chemistry / Q000187:drug effects; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced; D006213:Hallucinogens / Q000378:metabolism* / Q000633:toxicity*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000378:metabolism* / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000523:psychology*; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D014443:Tyrosine / Q000097:blood
D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D006213:Hallucinogens; D009570:Nitriles; D012701:Serotonin; D014443:Tyrosine; C071192:entacapone; D006897:Hydroxyindoleacetic Acid; D002394:Catechol O-Methyltransferase; D018817:N-Methyl-3,4-methylenedioxyamphetamine