Current preclinical studies on neuroinflammation and changes in blood-brain barrier integrity by MDMA and methamphetamine.

The blood-brain barrier (BBB) is essential in the maintenance of brain homeostasis both by preserving normal brain functioning and also by protecting the brain from exposure to a range of potentially harmful substances. This review presents some of the evidence of BBB disruption following exposure to the substituted amphetamines 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and methamphetamine (METH), two drugs of abuse which are widely consumed recreationally by younger sectors of the population. Both MDMA and METH have been shown to produce disruption of the BBB as reflected by IgG extravasation and Evans Blue leakage. In particular, METH decreases the expression of basal lamina proteins associated with an increase in matrix metalloproteinase activity. These changes in BBB integrity appear to be related to MDMA-induced activation of the mitogen-activated protein kinase (MAPK) JNK1/2. The consequences of the disruption in the BBB by these two drugs remain to be established, but there is evidence in the literature that, at least in the case of METH, increased matrix metalloproteinase (MMP) activity may be related to increased behavioural sensitization and reward perhaps because of the modification of the passage of the drug into the CNS. In addition, the high incidence of AIDS-related neurologic disease in METH users may also be related to increased entry into the brain of virally derived neurotoxic products. This article is part of the Special Issue entitled 'CNS Stimulants'.

Cocaine potentiates MDMA-induced oxidative stress but not dopaminergic neurotoxicity in mice: implications for the pathogenesis of free radical-induced neurodegenerative disorders.

RATIONALE: The drugs of abuse 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy") and cocaine both increase the generation of free radicals, and in the case of MDMA, this increase in oxidative stress is involved in the dopaminergic neurotoxicity produced by the drug in mice. Oxidative stress processes are also involved in the pathogenesis of several neurodegenerative diseases. OBJECTIVES: We aimed to determine the consequences of the combined administration of MDMA and cocaine on oxidative stress and dopaminergic neurotoxicity. METHODS: Mice received MDMA (20 mg/kg, i.p.; two doses separated by 3 h) followed by cocaine 1, 3, 6, or 24 h after the second MDMA dose. Mice were killed between 1 h and 7 days after cocaine injection. RESULTS: MDMA decreased dopamine transporter density and dopamine concentration 7 days later. Cocaine did not alter this neurotoxicity. MDMA produced an increase in the concentration of 2,3-dihydroxybenzoic acid in striatal microdialysis samples and an increase in lipid peroxidation in the striatum which were potentiated by cocaine. MDMA and cocaine given together also increased nitrate and 3-nitrotyrosine levels compared with either drug given alone. On the other hand, MDMA increased superoxide dismutase activity and decreased catalase activity, changes which were prevented by cocaine administration. In addition, cocaine administration produced an increase in glutathione peroxidase (GPx) activity in both saline-treated and MDMA-treated mice. CONCLUSIONS: Cocaine potentiates MDMA-induced oxidative stress but does not produce an increase in the neurotoxicity produced by MDMA, and this lack of potentiation may involve an increase in GPx activity.

Dopamine D2-receptor knockout mice are protected against dopaminergic neurotoxicity induced by methamphetamine or MDMA.

Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA), amphetamine derivatives widely used as recreational drugs, induce similar neurotoxic effects in mice, including a marked loss of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum. Although the role of dopamine in these neurotoxic effects is well established and pharmacological studies suggest involvement of a dopamine D2-like receptor, the specific dopamine receptor subtype involved has not been determined. In this study, we used dopamine D2 receptor knock-out mice (D2R(-/-)) to determine whether D2R is involved in METH- and MDMA-induced hyperthermia and neurotoxicity. In wild type animals, both drugs induced marked hyperthermia, decreased striatal dopamine content and TH- and DAT-immunoreactivity and increased striatal GFAP and Mac-1 expression as well as iNOS and interleukin 15 at 1 and 7days after drug exposure. They also caused dopaminergic cell loss in the SNpc. Inactivation of D2R blocked all these effects. Remarkably, D2R inactivation prevented METH-induced loss of dopaminergic neurons in the SNpc. In addition, striatal dopamine overflow, measured by fast scan cyclic voltammetry in the presence of METH, was significantly reduced in D2R(-/-) mice. Pre-treatment with reserpine indicated that the neuroprotective effect of D2R inactivation cannot be explained solely by its ability to prevent METH-induced hyperthermia: reserpine lowered body temperature in both genotypes, and potentiated METH toxicity in WT, but not D2R(-/-) mice. Our results demonstrate that the D2R is necessary for METH and MDMA neurotoxicity and that the neuroprotective effect of D2R inactivation is independent of its effect on body temperature.

Selective vulnerability in striosomes and in the nigrostriatal dopaminergic pathway after methamphetamine administration : early loss of TH in striosomes after methamphetamine.

Methamphetamine (METH), a commonly abused psychostimulant, causes dopamine neurotoxicity in humans, rodents, and nonhuman primates. This study examined the selective neuroanatomical pattern of dopaminergic neurotoxicity induced by METH in the mouse striatum. We examined the effect of METH on tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunoreactivity in the different compartments of the striatum and in the nucleus accumbens. The levels of dopamine and its metabolites, 3,4-dihidroxyphenylacetic acid and homovanillic acid, as well as serotonin (5-HT) and its metabolite, 5-hydroxyindolacetic acid, were also quantified in the striatum. Mice were given three injections of METH (4 mg/kg, i.p.) at 3 h intervals and sacrificed 7 days later. This repeated METH injection induced a hyperthermic response and a decrease in striatal concentrations of dopamine and its metabolites without affecting 5-HT concentrations. In addition, the drug caused a reduction in TH- and DAT-immunoreactivity when compared to saline-treated animals. Interestingly, there was a significantly greater loss of TH- and DAT-immunoreactivity in striosomes than in the matrix. The predominant loss of dopaminergic terminals in the striosomes occurred along the rostrocaudal axis of the striatum. In contrast, METH did not decrease TH- or DAT-immunoreactivity in the nucleus accumbens. These results provide the first evidence that compartments of the mouse striatum, striosomes and matrix, and mesolimbic and nigrostriatal pathways have different vulnerability to METH. This pattern is similar to that observed with other neurotoxins such as MPTP, the most widely used model of Parkinson's disease, in early Huntington's disease and hypoxic/ischemic injury, suggesting that these conditions might share mechanisms of neurotoxicity.

A study on the mechanisms by which minocycline protects against MDMA ('ecstasy')-induced neurotoxicity of 5-HT cortical neurons.

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') is a selective 5-HT neurotoxin in rat brain which has been shown to produce acute neuroinflammation characterized by activation of microglia and release of interleukin-1beta (IL-1beta). We aimed to determine whether or not minocycline, a semi-synthetic tetracycline antibiotic capable of inhibiting microglial activation, could prevent the inflammatory response and reduce the toxicity induced by MDMA. Adult male Dark Agouti rats were given minocycline twice a day for 2 days (45 mg/kg on the first day and 90 mg/kg on the second day; 12-h apart, i.p.). MDMA (12.5 mg/kg; i.p.) was given after the third minocycline injection and animals were killed either 1 h later for the determination of NFkappaB binding activity, 3 h later for the determination of IL-1beta, 24 h later for the determination of microglial activation or 7 days later for the determination of [(3)H]-paroxetine binding as a measure of 5-HT neurotoxicity. MDMA increased NFkappaB activation, IL-1beta release and microglial activation both in the frontal cortex and in the hypothalamus and 7 days later produced a reduction in the density of 5-HT uptake sites in both these brain areas. Minocycline prevented the MDMA-induced increase in NFkappaB activation, IL-1beta release and microglial activation in the frontal cortex and prevented the 5-HT neurotoxicity 7 days later. However, in the hypothalamus, in spite of preventing MDMA-induced microglial activation, minocycline failed to prevent MDMA-induced NFkappaB activation, IL-1beta release and neurotoxicity. This suggests that the protective mechanism of minocycline against MDMA-induced neurotoxicity in frontal cortex involves inhibition of MDMA-induced NFkappaB activation possibly through a reduction in IL-1beta signalling.

Mice with decreased cerebral dopamine function following a neurotoxic dose of MDMA (3,4-methylenedioxymethamphetamine, "Ecstasy") exhibit increased ethanol consumption and preference.

MDMA (3,4-methylenedioxymethamphetamine, "ecstasy") administration to mice produces relatively selective long-term neurotoxic damage to dopaminergic pathways. There is strong evidence indicating that the dopamine system plays a key role in the rewarding effects of ethanol and modulates ethanol intake. Using a two-bottle free-choice paradigm, we examined the voluntary consumption and preference for ethanol in mice deficient in cerebral dopamine concentration and dopamine transporter density by previous repeated MDMA administration. The current study shows that mice pre-exposed to a neurotoxic dose of MDMA exhibited a higher consumption of and preference for ethanol compared with saline-treated animals. The D(1) receptor full agonist SKF81297 [(6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide)] attenuated the enhanced ethanol intake, an effect that was reversed by SCH23390 [((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride], a D(1) receptor antagonist. MDMA-exposed mice also showed a reduced release of basal dopamine in the nucleus accumbens compared with saline-injected animals and a modest increase in D(1) receptor density in caudate-putamen and nucleus accumbens. Intraperitoneal administration of ethanol elevated extracellular dopamine release in the nucleus accumbens of saline-treated mice, but this effect was almost abolished in MDMA-treated mice. Differences between saline- and MDMA-treated animals did not appear to be secondary to changes in acute ethanol clearance. These results indicate that mice with reduced dopamine activity following a neurotoxic dose of MDMA exhibit increased ethanol consumption and preference and suggest that animals might need to consume more alcohol to reach the threshold for the rewarding effects of ethanol.

Evidence for a role of Hsp70 in the neuroprotection induced by heat shock pre-treatment against 3,4-methylenedioxymethamphetamine toxicity in rat brain.

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') produces acute hyperthermia which increases the severity of the selective serotoninergic neurotoxicity produced by the drug in rats. Heat shock protein 70 (Hsp70) is a major inducible cellular protein expressed in stress conditions and which is thought to exert protective functions. MDMA (12.5 mg/kg, i.p.), given to rats housed at 22 degrees C, produced an immediate hyperthermia and increased Hsp70 in frontal cortex between 3 h and 7 days after administration. MDMA, given to rats housed at low ambient temperature (4 degrees C) produced transient hypothermia followed by mild hyperthermia but no increase in Hsp70 expression, while rats treated at elevated room temperature (30 degrees C) showed enhanced hyperthermia and similar expression of Hsp70 to that seen in rats housed at 22 degrees C. Fluoxetine-induced inhibition of 5-HT release and hydroxyl radical formation did not modify MDMA-induced Hsp70 expression 3 h later. Four- or 8-day heat shock (elevation of basal rectal temperature by 1.5 degrees C for 1 h) or geldanamycin pre-treatment induced Hsp70 expression and protected against MDMA-induced serotoninergic neurotoxicity without affecting drug-induced hyperthermia. Thus, MDMA-induced Hsp70 expression depends on the drug-induced hyperthermic response and not on 5-HT release or hydroxyl radical formation and pre-induction of Hsp70 protects against the long-term serotoninergic damage produced by MDMA.

Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain.

RATIONALE: Ecstasy abuse commonly occurs in hot, overcrowded environments in combination with alcohol. Around 90% of ecstasy users take ethanol; over 70% of these users also often drink alcohol at hazardous levels. OBJECTIVES: We wished to examine whether binge ethanol administration enhanced the long-lasting 5-HT neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats maintained at high ambient temperature and the role of acetaldehyde. MATERIALS AND METHODS: Rats were treated with a 4-day ethanol regimen leading to plasma ethanol levels of around 450 mg/dl. On day 5, rats were placed at 30 degrees C and administered MDMA (5 mg/kg). Rectal temperature and hydroxyl radical formation were measured immediately before and up to 6 h after MDMA. 5-HT concentration and 5-HT transporter density were determined 7 days later. A group of rats received cyanamide (50 mg/kg) on days 1 and 3 of the 4-day-ethanol inhalation. RESULTS: In ethanol treated rats, MDMA produced a hyperthermic response similar to that observed in controls but enhanced the loss of 5-HT concentration and 5-HT transporter density in the hippocampus. Cyanamide elevated the plasma acetaldehyde concentration fivefold to sevenfold, reduced the MDMA-induced hyperthermia and increased the neuronal damage with neurotoxicity also appearing in the cortex. MDMA increased hydroxyl radical production in the hippocampus, the effect being more marked in rats pre-exposed to ethanol. CONCLUSIONS: Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity by a mechanism not related to changes in acute hyperthermia but probably involving hydroxyl radical formation. The magnitude of this effect is more pronounced after increasing plasma acetaldehyde levels by aldehyde dehydrogenase inhibition.

The acute and long-term neurotoxic effects of MDMA on marble burying behaviour in mice.

When mice are exposed to harmless objects such as marbles in their cage they bury them, a behaviour sometimes known as defensive burying. We investigated the effect of an acute dose of MDMA (èecstasy') and other psychoactive drugs on marble burying and also examined the effect of a prior neurotoxic dose of MDMA or p-chloroamphetamine (PCA) on burying. Acute administration of MDMA produced dose-dependent inhibition of marble burying (EC50: 7.6 micro mol/kg). Other drugs that enhance monoamine function also produced dose-dependent inhibition: methamphetamine PCA paroxetine MDMA GBR 12909 methylphenidate. None of these drugs altered locomotor activity at a dose that inhibited burying. A prior neurotoxic dose of MDMA, which decreased striatal dopamine content by 60%, but left striatal 5-HT content unaltered, did not alter spontaneous marble burying 18 or 40 days later. However, a neurotoxic dose of PCA which decreased striatal dopamine by 60% and striatal 5-HT by 70% attenuated marble burying 28 days later. Overall, these data suggest that MDMA, primarily by acutely increasing 5-HT function, acts like several anxiolytic drugs in this behavioural model. Long-term loss of cerebral 5-HT content also produced a similar effect. Since this change was observed only after 28 days, it is probably due to an adaptive response in the brain.

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 (>or=20 degrees C), but hypothermia when in cool conditions (Ta

Elevation of ambient room temperature has differential effects on MDMA-induced 5-HT and dopamine release in striatum and nucleus accumbens of rats.

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 30 degrees C) 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 30 degrees C. 5-HT release was also increased by MDMA given at 30 degrees C. In contrast, MDMA-induced extracellular dopamine and 5-HT increases in the striatum were unaffected by ambient temperature. At 20 degrees C room temperature, MDMA did not modify the rectal temperature but at 30 degrees C it produced a rapid and sustained hyperthermia. MDMA at 20 degrees C room temperature produced a two-fold increase in activity compared with saline-treated controls. The MDMA-induced increase in locomotor activity was more marked at 30 degrees C 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.

The role of 5-HT in the impairment of thermoregulation observed in rats administered MDMA ('ecstasy') when housed at high ambient temperature.

RATIONALE: Administration to rats of a neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) produces an impairment in thermoregulation which is reflected in a prolonged hyperthermic response to a subsequent dose of MDMA given to rats housed at high ambient temperature. OBJECTIVE: We wished to examine whether the impaired thermoregulation was associated with decreased cerebral 5-HT content produced by the prior neurotoxic dose of MDMA. METHODS: Rats were injected with drugs decreasing 5-HT function [the tryptophan hydroxlase inhibitor p-chlorophenylalanine (PCPA), and 5-HT receptor antagonists] and rectal temperature was measured after administering MDMA to rats housed at 30 degrees C. RESULTS: PCPA pretreatment decreased 5-HT and 5-HIAA concentrations in cortex, hippocampus and striatum by >80% and prolonged the hyperthermia induced in rats housed at 30 degrees C by administering MDMA (5 mg/kg i.p.). A similar prolongation of the hyperthermic response to MDMA was seen when rats were pretreated with methysergide (10 mg/kg i.p.) or the 5-HT(1A) antagonist WAY100635 (0.5 mg/kg s.c.). CONCLUSIONS: Decreasing 5-HT function in diverse ways enhanced the hyperthermic response to MDMA given to rats housed at high ambient temperature. This suggests that loss of 5-HT acting on 5-HT(1A) receptors leads to impaired thermoregulation in rats and suggests that the impairment seen in MDMA pretreated rats housed at high ambient temperature is due to a loss in 5-HT function. These data could have implications for recreational users of MDMA, who may have damaged serotoninergic neurons because of prior heavy or frequent use of the drug, when taking further doses of MDMA in hot environments such as dance clubs.

A review of the mechanisms involved in the acute MDMA (ecstasy)-induced hyperthermic response.

The predominant severe acute adverse effect following ingestion of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) by recreational users is hyperthermia which can induce other associated clinical problems and occasionally death. There is no pharmacologically specific treatment. MDMA also induces dose-dependent hyperthermia in experimental animals. This review examines the consequences of MDMA administration on body temperature in humans and rodents. In rats hyperthermia results primarily from dopamine release and is influenced by dose, ambient temperature and other housing conditions. The response is increased in rats with a prior MDMA-induced neurotoxic lesion of 5-hydroxytryptamine (5-HT) nerve endings. Increased MDMA-induced locomotor activity appears to play no role in the hyperthermic response. However, the size of the acute hyperthermic response plays a major role in determining the severity of the subsequent neurotoxicity. These results suggest that any MDMA-induced hyperthermic response will be enhanced in hot, crowded dance club conditions and that ingesting the drug in such conditions increases the possibility of subsequent cerebral neurotoxic effect.

Effect of repeated ('binge') dosing of MDMA to rats housed at normal and high temperature on neurotoxic damage to cerebral 5-HT and dopamine neurones.

The technique of 'binge' dosing (several doses in one session) by recreational users of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) requires evaluation in terms of its consequences on the acute hyperthermic response and long-term neurotoxicity. We examined the neurotoxic effects of this dosing schedule on 5-HT and dopamine neurones in the rat brain. When repeated (three) doses of MDMA (2, 4 and 6 mg/kg i.p.) were given 3 h apart to rats housed at 19 degrees C, a dose-dependent acute hyperthermia and long-term loss of 5-HT was observed in several brain regions (hippocampus, cortex and striatum), with an approximate 50% loss following 3 x 4 mg/kg and 65% decrease following 3 x 6 mg/kg. No decrease in striatal dopamine content was detected. When MDMA (4 mg/kg i.p.) was given repeatedly to rats housed at 30 degrees C, a larger acute hyperthermic response than that observed in rats treated at 19 degrees C environment was seen (maximum response 2.6 +/- 0.1 degrees C versus 1.3 +/- 0.2 degrees C). A long-term cerebral 5-HT loss of approximately 65% was also detected in both the cortex and hippocampus, but no loss in striatal dopamine content occurred. These data emphasize the increased acute hyperthermic response and neurotoxicity which occurs when MDMA is administered in a hot room environment compared to normal room temperature conditions, and support the view that MDMA is a selective 5-HT neurotoxin, even when a binge dosing schedule is employed and the rats are present in a hot environment.

3,4-Methylenedioxymethamphetamine increases interleukin-1beta levels and activates microglia in rat brain: studies on the relationship with acute hyperthermia and 5-HT depletion.

3,4-Methylenedioxymethamphetamine (MDMA) administration to rats produces acute hyperthermia and 5-HT release. Interleukin-1beta (IL-1beta) is a pro-inflammatory pyrogen produced by activated microglia in the brain. We examined the effect of a neurotoxic dose of MDMA on IL-1beta concentration and glial activation and their relationship with acute hyperthermia and 5-HT depletion. MDMA, given to rats housed at 22 degrees C, increased IL-1beta levels in hypothalamus and cortex from 1 to 6 h and [(3)H]-(1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)3-isoquinolinecarboxamide) binding 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-1beta release is a consequence, not the cause, of the rise in body temperature. When MDMA was given to rats housed at 4 degrees C, hyperthermia was abolished and the IL-1beta increase significantly reduced. The MDMA-induced acute 5-HT depletion was prevented by fluoxetine coadministration but the IL-1beta increase and hyperthermia were unaffected. Therefore, the rise in IL-1beta is not related to the acute 5-HT release but is linked to the hyperthermia. Contrary to IL-1beta 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.

Acute and long-term effects of MDMA on cerebral dopamine biochemistry and function.

RATIONALE AND OBJECTIVES: The majority of experimental and clinical studies on the pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) tend to focus on its action on 5-HT biochemistry and function. However, there is considerable evidence for MDMA having marked acute effects on dopamine release. Furthermore, while MDMA produces long-term effects on 5-HT neurones in most species examined, in mice its long-term effects appear to be restricted to the dopamine system. The objective of this review is to examine the actions of MDMA on dopamine biochemistry and function in mice, rats, guinea pigs, monkeys and humans. RESULTS AND DISCUSSION: MDMA appears to produce a major release of dopamine from its nerve endings in all species investigated. This release plays a significant role in the expression of many of the behaviours that occur, including behavioural changes, alterations of the mental state in humans and the potentially life-threatening hyperthermia that can occur. While MDMA appears to be a selective 5-HT neurotoxin in most species examined (rats, guinea pigs and primates), it is a selective dopamine neurotoxin in mice. Selectivity may be a consequence of what neurotoxic metabolites are produced (which may depend on dosing schedules), their selectivity for monoamine nerve endings, or the endogenous free radical trapping ability of specific nerve endings, or both. We suggest more focus be made on the actions of MDMA on dopamine neurochemistry and function to provide a better understanding of the acute and long-term consequences of using this popular recreational drug.

Effect of ambient temperature and a prior neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA) on the hyperthermic response of rats to a single or repeated ('binge' ingestion) low dose of MDMA.

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) administration to rats produces acute hyperthermia and long-term neurotoxic damage to 5-hydroxytryptamine (serotonin, 5-HT) neurones. OBJECTIVE: We wished to examine MDMA-induced hyperthermia in rats housed at normal (19 degrees C) and high (30 degrees C) room temperatures and investigate the effect of a prior neurotoxic lesion. METHODS: Rectal temperature was measured after administration of single or repeated doses of MDMA to rats housed at 19 degrees C and 30 degrees C. RESULTS: MDMA (5 mg/kg i.p.) produced a sustained hyperthermic response in rats housed at 30 degrees C, but not in rats housed at 19 degrees C. A prior (5 weeks earlier) neurotoxic dose of MDMA (12.5 mg/kg i.p.) resulted in MDMA (5 mg/kg) producing a greater hyperthermic response in rats housed at 30 degrees C than in non-pre-treated animals. Repeated MDMA administration (binge dosing; 2, 4 or 6 mg/kg x3) produced dose-dependent hyperthermia in rats housed at 19 degrees C, with MDMA (2 mg/kg x3) having little effect. However, this dose produced significant hyperthermia (> or =2 degrees C above control values)in rats housed at 30 degrees C following the third dose. A prior neurotoxic dose of MDMA resulted in MDMA (2 mg/kg x3) producing marked hyperthermia (>1 degrees C) after the first dose and severe hyperthermia (> or =2 degrees C) after the third dose. CONCLUSIONS: MDMA administration to rats housed at 30 degrees C produces a more severe hyperthermic response than that seen in rats housed at 19 degrees C. A prior neurotoxic dose enhances the response further in animals housed at 30 degrees C. Binge dosing produces a higher final peak response than a similar non-divided dose. This effect is more marked in animals housed at high room temperature. These data may have implications for recreational users of MDMA in hot environments, particularly those who may have damaged serotoninergic neurones because of prior heavy or frequent use of the drug.

Inhibition of glutamate release by delaying ATP fall accounts for neuroprotective effects of antioxidants in experimental stroke.

Excitotoxic neuronal injury related to excessive glutamate release is believed to play a key role in the pathogenesis of focal cerebral ischemia. Reversal of neuronal glutamate transporters caused by ATP fall and subsequent imbalance of membrane ionic gradients accounts for most glutamate release after cerebral ischemia. ATP synthesis from oxidative phosphorylation derives from the coupled functioning of the mitochondrial respiratory chain (MRC) and the ATP synthase; interestingly, the MRC is one of the main sites of cellular reactive oxygen species (ROS) generation even in physiological circumstances. Hence, we have studied the effect of the antioxidants glutathione, superoxide dismutase, and alpha-tocopherol on infarct outcome, brain ATP, and glutamate levels after permanent middle cerebral artery occlusion (MCAO) in Fischer rats; we have also characterized the actions of antioxidants on MRC complexes. Our results show that intraperitoneal administration of antioxidants 2 h before MCAO enhances ATP synthesis and causes a neuroprotective effect concomitant to inhibition of ischemia-induced increase in brain glutamate. Antioxidants also increased mitochondrial ATP and MRC complex I-III activity and respiration, suggesting that these actions are due to removal of the inhibition caused by endogenous ROS on MRC. These findings may possess important therapeutic repercussions in the management of ischemic stroke.