3,4-Methylenedioxymethamphetamine (MDMA) administration to rats produces acute hyperthermia and 5-HT release. Interleukin-1b (IL-1b) is a pro-inflammatory pyrogen produced by activated microglia in the brain. We examined the effect of a neurotoxic dose of MDMA on IL-1b concentration and glial activation and their relationship with acute hyperthermia and 5-HT depletion. MDMA, given to rats housed at 22°C, increased IL-1b levels in hypothalamus and cortex from 1 to 6 h andbinding between 3 and 48 h. Increased immunoreactivity to OX-42 was also detected. Rats became hyperthermic immediately after MDMA and up to at least 12 h later. The IL-1 receptor antagonist did not modify MDMA-induced hyperthermia indicating that IL-1b release is a consequence, not the cause, of the rise in body temperature. When MDMA was given to rats housed at 4°C, hyperthermia was abolished and the IL-1b increase significantly reduced. The MDMA-induced acute 5-HT depletion was prevented by fluoxetine coadministration but the IL-1b increase and hyperthermia were unaffected. Therefore, the rise in IL-1b is not related to the acute 5-HT release but is linked to the hyperthermia. Contrary to IL-1b levels, microglial activation is not significantly modified when hyperthermia is prevented, suggesting that it might be a process not dependent on the hyperthermic response induced by MDMA.

3,4-Methylenedioxymethamphetamine (MDMA) produces acute dopamine and 5-HT release in rat brain and a hyperthermic response, which is dependent on the ambient room temperature in which the animal is housed. We examined the effect of ambient room temperature (20 and 301C) on MDMA-induced dopamine and 5-HT efflux in the striatum and shell of nucleus accumbens (NAc) of freely moving rats by using microdialysis. Locomotor activity and rectal temperature were also evaluated. In the NAc, MDMA (2.5 or 5 mg/kg, i.p.) produced a substantial increase in extracellular dopamine, which was more marked at 301C. 5-HT release was also increased by MDMA given at 301C. In contrast, MDMA-induced extracellular dopamine and 5-HT increases in the striatum were unaffected by ambient temperature. At 201C room temperature, MDMA did not modify the rectal temperature but at 301C it produced a rapid and sustained hyperthermia. MDMA at 201C room temperature produced a two-fold increase in activity compared with salinetreated controls. The MDMA-induced increase in locomotor activity was more marked at 301C due to a decrease in the activity of the saline-treated controls at this high ambient temperature. These results show that high ambient temperature enhances MDMA-induced locomotor activity and monoamine release in the shell of NAc, a region involved in the incentive motivational properties of drugs of abuse, and suggest that the rewarding effects of MDMA may be more pronounced at high ambient temperature.

1 This study investigated whether the immediate and long-term effects of 3,4-methylenedioxymethamphetamine (MDMA) on monoamines in mouse brain are due to the parent compound and the possible contribution of a major reactive metabolite, 3,4-dihydroxymethamphetamine (HHMA), to these changes. The acute effect of each compound on rectal temperature was also determined. 2 MDMA given i.p. (30 mg kg À1, three times at 3-h intervals), but not into the striatum (1, 10 and 100 mg, three times at 3-h intervals), produced a reduction in striatal dopamine content and modest 5-HT reduction 1 h after the last dose. MDMA does not therefore appear to be responsible for the acute monoamine release that follows its peripheral injection. 3 HHMA does not contribute to the acute MDMA-induced dopamine depletion as the acute central effects of MDMA and HHMA differed following i.p. injection. Both compounds induced hyperthermia, confirming that the acute dopamine depletion is not responsible for the temperature changes. 4 Peripheral administration of MDMA produced dopamine depletion 7 days later. Intrastriatal MDMA administration only produced a long-term loss of dopamine at much higher concentrations than those reached after the i.p. dose and therefore bears little relevance to the neurotoxicity. This indicates that the long-term effect is not attributable to the parent compound. HHMA also appeared not to be responsible as i.p. administration failed to alter the striatal dopamine concentration 7 days later.

The amphetamine analogue 3,4‐methylenedioxymethamphetamine (MDMA or “Ecstasy”) is a popular drug of abuse which causes different neurotoxic effects in the mouse compared with the rat. In mice, MDMA produces damage to striatal dopamine terminals, having little long‐term effects on serotonin (5‐HT) containing neurons. A relevant feature of the striatum is its striosome/matrix compartmental organization; defined by different connexions, and functions. In this study we examined the long‐term effect induced by MDMA on tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunoreactivity in the striosomes and matrix compartments of mouse striatum. Mice given MDMA showed significant reductions in TH and DAT immunostaining in striatum compared with control animals. Interestingly, this effect was considerably more pronounced in striosomes than in the matrix. These data provide the first evidence that striosomes and matrix compartments of the mouse striatum have differential vulnerability to MDMA and that the long‐term neurotoxicity induced by MDMA in mice is primarily associated with a loss of striosomal dopamine fibres. Synapse 62:80–84, 2008. © 2007 Wiley‐Liss, Inc.

1 3,4-Methylenedioxymethamphetamine (MDMA or 'ecstasy') decreases the 5-HT concentration, [ 3 H]-paroxetine binding and tryptophan hydroxylase activity in rat forebrain, which has been interpreted as indicating 5-HT neurodegeneration. This has been questioned, particularly the 5-HT loss, as MDMA can also inhibit tryptophan hydroxylase. We have now evaluated the validity of these parameters as a reflection of neurotoxicity. 2 Male DA rats were administered MDMA (12.5 mg kg À1 , i.p.) and killed up to 32 weeks later. 5-HT content and [ 3 H]-paroxetine binding were measured in the cortex, hippocampus and striatum. Parallel groups of treated animals were administered NSD-1015 for determination of in vivo tryptophan hydroxylase activity and 5-HT turnover rate constant. 3 Tissue 5-HT content and [ 3 H]-paroxetine binding were reduced in the cortex (26-53%) and hippocampus (25-74%) at all time points (1, 2, 4, 8 and 32 weeks). Hydroxylase activity was similarly reduced up to 8 weeks, but had recovered at 32 weeks. The striatal 5-HT concentration and [ 3 H]-paroxetine binding recovered by week 4 and hydroxylase activity after week 1. In all regions, the reduction in 5-HT concentration did not result in an altered 5-HT synthesis rate constant. 4 Administering MDMA to animals when housed at 41C prevented the reduction in [ 3 H]-paroxetine binding and hydroxylase activity observed in rats housed at 221C, but not the reduction in 5-HT concentration. 5 These data indicate that MDMA produces long-term damage to serotoninergic neurones, but this does not produce a compensatory increase in 5-HT synthesis in remaining terminals. It also highlights the fact that measurement of tissue 5-HT concentration may overestimate neurotoxic damage.