British Journal of Pharmacology
January 1, 2002
Annis O. Mechan, B. Moreno Esteban, Esther O’shea et al.
219 citations
MDMA (ecstasy) causes acute hyperthermia in rats by increasing dopamine release, which acts on D1 receptors, rather than through serotonin release. Blocking serotonin receptors or inhibiting serotonin reuptake did not prevent the rise in body temperature, but blocking D1 dopamine receptors with SCH 23390 did. The tail skin temperature did not increase, suggesting MDMA impairs heat dissipation. These findings indicate that dopamine, not serotonin, is the primary driver of MDMA-induced hyperthermia, which has implications for clinical treatment.
British Journal of Pharmacology
June 1, 1997
M. Isabel Colado, Esther O’shea, R Granados et al.
176 citations
High doses of MDMA (ecstasy) given to pregnant rats on days 14–17 of gestation caused a marked hyperthermic response in the mothers, reduced their body weight, and decreased litter size by about 20%. In the mothers' brains, serotonin (5-HT) and its metabolite 5-HIAA fell by over 65% in the hippocampus and striatum and by 40% in the cortex one week after birth. However, the brains of the newborn pups showed no such decreases. MDMA also increased lipid peroxidation (TBARS) in the cortex of adult rats but not in 7–10 day old neonates.
British Journal of Pharmacology
August 1, 1995
M. Isabel Colado, Jodi L. Williams, A.r. Green
165 citations
In Dark Agouti rats, female animals had 57% higher plasma MDMA concentrations and 48% lower MDA concentrations than males 45 minutes after injection, and showed a stronger hyperthermic response to MDMA. This suggests impaired N-demethylation in females, which model the human poor metabolizer phenotype for debrisoquine 4-hydroxylase. A single 10 mg/kg dose of MDMA caused substantial loss of serotonin and its metabolite in cortex and hippocampus seven days later, along with a 27% decrease in [3H]-paroxetine binding, indicating neurodegeneration. MDA at 5 mg/kg produced about 40% serotonin loss in both sexes. Low debrisoquine hydroxylase activity did not prevent formation of neurotoxic metabolites.
British Journal of Pharmacology
December 1, 2001
M. Isabel Colado, Jorge Camarero, Annis O. Mechan et al.
122 citations
MDMA (ecstasy) causes long-term damage to dopamine nerve terminals in the mouse striatum, accompanied by acute hyperthermia. Blocking NMDA receptors or using clomethiazole did not protect against this damage. The free radical trap PBN and the nitric oxide synthase inhibitor 7-NI were protective but also lowered body temperature. Two other NOS inhibitors, S-methyl-L-thiocitrulline and AR-R17477AR, provided significant neuroprotection with little effect on hyperthermia. MDMA increased free radical formation in the striatum, which was prevented by AR-R17477AR, which lacks radical-trapping activity. This suggests MDMA neurotoxicity involves radicals from MDMA or dopamine metabolites combining with nitric oxide to form damaging peroxynitrites.
Neurobiology of Disease
March 22, 2021
Noelia Granado, Sara Ares-Santos, Idaira Oliva et al.
117 citations
The dopamine D2 receptor is necessary for the neurotoxic effects of methamphetamine and MDMA (ecstasy) in mice. In wild-type mice, both drugs caused hyperthermia, loss of dopamine markers (tyrosine hydroxylase and dopamine transporter) in the striatum, inflammation, and dopaminergic cell death in the substantia nigra pars compacta. In mice lacking the D2 receptor (D2R−/−), all these effects were blocked, including the loss of dopaminergic neurons. The neuroprotective effect of D2R inactivation was not solely due to preventing hyperthermia, as reserpine lowered body temperature in both genotypes but potentiated toxicity only in wild-type mice. These results indicate that D2R is essential for methamphetamine and MDMA neurotoxicity, independent of body temperature.
Journal of Neurochemistry
September 24, 2008
Noelia Granado, Esther O’shea, Jordi Bové et al.
112 citations
Repeated doses of MDMA (ecstasy) given to mice cause a lasting loss of dopamine-producing neurons in the substantia nigra, a brain region critical for movement. One day after injection, the number of these neurons drops and remains low for at least 30 days. In the striatum, markers of dopamine function also fall sharply within a day and stay reduced for a month, though some recovery begins after three days, with new nerve fiber growth. Damage is selective: the nucleus accumbens is unaffected, showing MDMA destroys the nigrostriatal pathway but spares the mesolimbic pathway. Immune cell activation follows the same pattern, confirming the link between inflammation and dopamine cell death.
British Journal of Pharmacology
September 1, 2001
Violeta Sánchez Sánchez, Jorge Camarero, B. Moreno Esteban et al.
103 citations
Fluoxetine provides long-lasting protection against MDMA-induced damage to serotonin nerve endings in rat brain, while fluvoxamine only protects when given at the same time. MDMA caused loss of serotonin and its metabolite in cortex, hippocampus, and striatum, and reduced paroxetine binding one week later. Fluoxetine given with MDMA or up to four days before offered complete protection, and significant protection when given seven days before. Fluvoxamine required concurrent administration. Fluoxetine's protection appears due to its and its active metabolite's inhibition of the serotonin transporter, not by altering MDMA accumulation or metabolism.
British Journal of Pharmacology
July 4, 2005
A Richard Green, Esther O’shea, Kathryn S. Saadat et al.
70 citations
In rats, MDMA (ecstasy) causes hyperthermia at normal or warm room temperatures but hypothermia in cool conditions. At 15°C, MDMA rapidly lowered rectal temperature; this effect was blocked by a dopamine D2 receptor antagonist but not a D1 antagonist. A neurotoxic MDMA regimen reduced serotonin in the brain by about 30% after a week. This serotonin lesion did not affect tail temperature increases when rats moved from 20°C to 30°C, but led to lower tail temperatures when returned to 24°C. Acute MDMA in lesioned rats at 30°C caused a sustained drop in tail temperature. The findings suggest that thermoregulatory problems in MDMA-lesioned rats stem partly from impaired heat loss through the tail, a key heat-loss organ.
Journal of Psychopharmacology
September 1, 2004
Verónica Sánchez, Esther O’shea, Kathryn S. Saadat et al.
66 citations
Repeated doses of MDMA (ecstasy) given to rats in a single session cause a dose-dependent increase in body temperature and long-term damage to serotonin neurons in the brain, but not to dopamine neurons. A dosing schedule of three injections of 4 mg/kg led to about a 50% loss of serotonin in the hippocampus, cortex, and striatum, while three injections of 6 mg/kg led to about a 65% loss. When rats were housed in a hot environment (30 °C), the same dose produced a larger temperature increase (up to 2.6 °C) and a 65% loss of serotonin in the cortex and hippocampus, with no loss of dopamine in the striatum.
Synapse
October 25, 2007
Noelia Granado, Isabel Escobedo, Esther O’shea et al.
59 citations
The drug MDMA (Ecstasy) damages dopamine nerve terminals in the mouse striatum, with a greater effect in striosomes—specialized brain compartments linked to different functions—than in the surrounding matrix. Mice given MDMA showed significant reductions in two markers of dopamine neurons, tyrosine hydroxylase and dopamine transporter, compared with controls. The loss was considerably more pronounced in striosomes, indicating that these compartments are more vulnerable to MDMA's long-term neurotoxicity. This provides the first evidence that striosome and matrix compartments differ in their sensitivity to MDMA, with the damage primarily involving striosomal dopamine fibers.