Studies on the effect of MDMA (‘ecstasy’) on the body temperature of rats housed at different ambient room temperatures

3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy') administration to rats produces hyperthermia if they are housed in normal or warm ambient room temperature (Ta) conditions (⩾20°C), but hypothermia when in cool conditions (Ta⩽17°C). We have now investigated some of the mechanisms involved. MDMA (5 mg kg−1 i.p.) produced a rapid decrease in rectal temperature in rats at Ta 15°C. This response was blocked by pretreatment with the dopamine D2 receptor antagonist remoxipride (10 mg kg−1 i.p.), but unaltered by pretreatment with the D1 antagonist {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 (1.1 mg kg−1 i.p.). MDMA (5 mg kg−1) did not alter the tail temperature of rats at Ta 15°C, but decreased the tail temperature of rats at Ta 30°C. A neurotoxic dose of MDMA (three doses of 5 mg kg−1 given 3 h apart) decreased cortical and hippocampal 5-HT content by approximately 30% 7 days later. This lesion did not influence the rise in tail temperature when rats were moved from Ta 20°C to 30°C compared to nonlesioned controls, but did result in a lower tail temperature than that of controls when they were returned to Ta 24°C. Acute administration of MDMA (5 mg kg−1) to MDMA-lesioned rats produced a sustained decrease in tail temperature in rats housed at Ta 30°C compared to nonlesioned controls. These data suggest that the thermoregulatory problems previously observed in MDMA-lesioned rats housed at Ta 30°C result, partially, from their inability to lose heat by vasodilation of the tail, a major heat-loss organ in this species. Keywords: 5-Hydroxytryptamine, hypothermia, hyperthermia, tail temperature, MDMA, ecstasy, dopamine, thermoregulation, neurotoxicity Introduction 3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy') is a drug widely used by young people, particularly in dance club situations. Administration of this compound to laboratory animals when the animals are present in a room at normal (20–22°C) ambient temperature (Ta) produces acute and rapid hyperthermia (Green et al., 2003; 2004b). Human recreational users of MDMA can also suffer an acute hyperthermic response which, if severe, can result in death (Schifano, 2004). There is also evidence that the MDMA-induced hyperthermic response in rats is enhanced when the animals are present at warm Ta (30°C) (Dafters, 1995; Malberg & Seiden, 1998; Green et al., 2004a). In contrast, when rats are housed in cool ambient room temperature conditions (Ta 17°C or lower), administration of MDMA induces a rapid hypothermic response (Gordon et al., 1991; Dafters, 1994; Dafters & Lynch, 1998). While previous work in our group indicated that the rapid increase in rectal temperature is associated with the increase in dopamine release induced by MDMA and its action on dopamine D1 receptors (Mechan et al., 2002), no investigation appears to have been made on the mechanisms involved in the hypothermic response seen in rats housed at cool Ta. Administration of large or repeated doses of MDMA produces a long-term neurotoxic loss of 5-HT in the forebrain (Green et al., 2003). When MDMA-lesioned rats are exposed to Ta 30°C and then returned to Ta 20°C, it takes longer for their body temperature (which has increased modestly in the warm conditions compared to rats housed at an ambient room temperature of 20°C) to return to normal, compared to nonlesioned control animals. This observation was made using two different experimental approaches. Dafters & Lynch (1998) measured the duration of the hyperthermic response in lesioned rats compared to the duration of the response in the same animals prior to the neurotoxic dose of MDMA, while Mechan et al. (2001) measured the rectal temperature of parallel groups that had been pretreated 4 weeks earlier with either saline or a lesioning dose of MDMA. Both groups of investigators concluded that MDMA-lesioned rats had problems in losing heat following exposure to hot temperature and a return to normal room temperature conditions. It was suggested that this problem might be associated with the decrease in cerebral 5-HT concentration. This problem of heat loss in lesioned rats when they are present in a warm environment was also seen in another type of study. Rats given a neurotoxic dose of MDMA 7 or more days earlier displayed a prolongation in the acute hyperthermic response, which followed a low challenge dose of MDMA when compared to saline-pretreated rats given the same challenge dose of MDMA. However, this effect was seen only in MDMA-lesioned rats housed at Ta 30°C and not when the animals were present at Ta 20°C (Green et al., 2004a). To further examine whether a loss in cerebral 5-HT concentration and therefore presumably function was involved in the abnormal thermoregulatory responses seen in MDMA-lesioned rats, we recently examined the effect on heat loss in rats housed at Ta 30°C of decreasing cerebral 5-HT function by prior injection of either the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) or certain 5-HT receptor antagonists. Pretreatment with PCPA, methysergide or WAY100635 had the effect of prolonging the hyperthermic response to a challenge dose of MDMA when the animals were in the warm room. This again suggested strongly that it was the decrease in 5-HT function produced by a neurotoxic dose of MDMA that was responsible for the impairment in the ability of rats to lose heat in hot Ta conditions. A decrease in cerebral 5-HT function produced by either MDMA or administration of PCPA or 5-HT antagonists did not, of itself, alter the body temperature of rats housed at Ta 30°C; a challenge of either a hyperthermia-producing acute dose of MDMA or a move to cooler room conditions was required to expose the defect in thermoregulation. In the current investigation, we have examined the effect of dopamine D1 and D2 receptor antagonists on the hypothermic response, which follows when MDMA is given to rats housed at Ta 15°C. Since heat loss in rats is primarily regulated by vasodilation of blood vessels in the tail, a major heat exchange organ in this species (Grant, 1963; Romanovsky et al., 2002), the current study has also examined the effect of an acute dose of MDMA on the tail temperature of rats exposed to warm and cool Ta, and the effect of a prior MDMA-induced neurotoxic lesion on this response.