Effect of 3,4-methylenedioxymethamphetamine ("ecstasy") on body temperature and liver antioxidant status in mice: influence of ambient temperature

Abstract

The consumption of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is known to cause severe hyperthermia and liver damage in humans. The thermogenic response induced by MDMA is complex and partially determined by the prevailing ambient temperature (AT). This is of extreme importance since ecstasy is often consumed at "rave" parties, where dancing takes place in a warm environment, which may exacerbate the effect of MDMA on thermoregulation. In view of the fact that hyperthermia is a well-known pro-oxidant aggressive condition, its potential role in ecstasy-induced hepatocellular toxicity should be further studied. Thus, the present study was performed in order to evaluate the influence of AT on the effects of single administration of MDMA on body temperature and liver toxicity in Charles River mice. Animals were given an acute intraperitoneal dose of MDMA (5, 10 or 20 mg/kg) and placed in AT of 20+/-2 degrees C or 30+/-2 degrees C for 24 h. Body temperature was measured during the study using implanted transponders and a temperature probe reading device. Plasma and liver samples were used for biochemical analysis. Liver sections were also taken for histological examination. The parameters evaluated were (1) plasma levels of transaminases and alkaline phosphatase, (2) hepatic glutathione (GSH), (3) hepatic lipid peroxidation, (4) activity of hepatic antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase, glutathione- S-transferase, copper/zinc superoxide dismutase and manganese superoxide dismutase), and (5) liver histology. The hyperthermic response elicited by MDMA was clearly dose-related and potentiated by high AT. Administration of MDMA produced some evidence of oxidative stress, expressed as GSH depletion at both ATs studied, as well as by lipid peroxidation and decreased catalase activity at high AT. High AT, by itself, decreased glutathione peroxidase activity. Histological examination of the liver revealed abnormalities of a dose- and AT-dependent nature. These changes included vacuolation of the hepatocytes, presence of blood clots and loss of typical hepatic cord organisation. The results obtained in the present study suggest that oxidative stress plays a part in the first stage of MDMA-induced liver damage and that liver antioxidant status is aggravated by increased AT. Thus, these findings are in accordance with the hypothesis that high AT may potentiate ecstasy-induced hepatotoxicity by increasing body hyperthermia.

The Pharmacology and Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”)

“…In contrast, the same laboratory (Johnson et al, 2002a) using male BALB/c mice and lower doses of MDMA (5 and 10 mg/kg s.c. every 2 h for 4 doses) observed a dose-dependent hypothermic response that was still evident 24 h after administration of the higher dose studied. Carvalho et al (2002) measured the subcutaneous temperature of male Charles River mice and reported that a single administration of MDMA (5,10, and 20 mg/kg i.p.) produced an increase in body temperature that reached its maximum (2°C) at approximately 30 min and remained elevated for more than 4 h. Using Swiss-Webster mice, O'Shea et al (2001) reported that repeated administration of MDMA (3 times at 3-h intervals i.p.)…”

Oral administration of (±)3,4-methylenedioxymethamphetamine and (+)methamphetamine alters temperature and activity in rhesus macaques

“…It is now well established that MDMA (considered the authentic compound in street "Ecstasy" tablets) can elevate temperature in humans (Freedman et al, 2005) and many other species (Brown and Kiyatkin, 2004;Carvalho et al, 2002;Dafters, 1994;Fantegrossi et al, 2003;Fiege et al, 2003;Pedersen and Blessing, 2001;Rosa-Neto et al, 2004;Saadat et al, 2004;Taffe et al, 2006). Methamphetamine (METH), which is often substituted for MDMA intentionally (Kelly et al, 2006;Levy et al, 2005;Wu et al, 2006) or otherwise (Baggott et al, 2000;Tanner-Smith, 2006) in the nightclub setting, likewise produces hyperthermia (Bowyer et al, 1994;Bowyer et al, 1992;Crean et al, 2006), in some cases to an unregulated and fatal degree (Madden et al, 2005;Ricaurte et al, 2003Ricaurte et al, ,2002Yuan et al, 2006).…”

Impact of Ambient Temperature on Hyperthermia Induced by (±)3,4-Methylenedioxymethamphetamine in Rhesus Macaques

“…The recreationally abused drug (7)3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') elevates body temperature in rats (Brown and Kiyatkin, 2004;Dafters, 1994;Malberg and Seiden, 1998), mice (Carvalho et al, 2002;Fantegrossi et al, 2003), guinea-pigs (Saadat et al, 2004), pigs (Fiege et al, 2003;Rosa-Neto et al, 2004), rabbits (Pedersen and Blessing, 2001), humans (Freedman et al, 2005), and rhesus macaques (Taffe et al, 2005). Sufficiently low ambient temperature conditions can prevent (7)MDMA from inducing hyperthermia or even result in hypothermia in rodent models (Dafters, 1994;Gordon et al, 1991;Miller and O'Callaghan, 1994).…”

“…Sufficiently low ambient temperature conditions can prevent (7)MDMA from inducing hyperthermia or even result in hypothermia in rodent models (Dafters, 1994;Gordon et al, 1991;Miller and O'Callaghan, 1994). Such effects can attenuate or prevent the occurrence of lasting changes, for example, in central nervous system (CNS) serotonin (rat) or dopamine (mouse) function (Carvalho et al, 2002;Malberg and Seiden, 1998;Miller and O'Callaghan, 1994). Similarly, elevations of ambient temperature (T A ) appear to increase the magnitude of MDMA-induced hyperthermia and the severity of observed alterations to monoaminergic neurotransmission in rodents.…”