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
July 1, 1997
María Isabel Colado, Esther O’shea, R Granados et al.
175 citations
MDMA (ecstasy) and p-chloroamphetamine (PCA) damage serotonin neurons in rat brain by increasing free radical formation, measured as 2,3-dihydroxybenzoic acid from salicylic acid via microdialysis in the hippocampus. A single dose of MDMA (15 mg/kg) raised 2,3-DHBA for at least 6 hours and reduced serotonin and its metabolite by over 50% in hippocampus, cortex, and striatum seven days later. PCA (5 mg/kg) also increased 2,3-DHBA. Fenfluramine (15 mg/kg) did not increase free radicals but still caused long-term serotonin loss. Pretreatment with fenfluramine blocked MDMA's free radical rise, indicating radicals originate in serotonin neurons. The free radical scavenger PBN prevented the acute radical increase and attenuated long-term hippocampal damage by 30%. Thus, MDMA and PCA damage serotonin neurons via free radicals, while fenfluramine acts through a different mechanism.
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
February 1, 1999
María Isabel Colado, Esther O’shea, R Granados et al.
82 citations
Dopamine does not appear to cause the damage to serotonin nerve endings that occurs in the brain of Dark Agouti rats after MDMA (ecstasy) administration. The drug haloperidol prevented both the acute rise in body temperature and the long-term loss of serotonin when given around the time of MDMA, but this protection was minimal when body temperature was kept high. MDMA increased dopamine levels in the brain by 800%, but boosting dopamine further with L-DOPA did not worsen the nerve damage, nor did it make a low, non-toxic dose of MDMA become toxic. The findings suggest that earlier studies linking dopamine to MDMA's neurotoxicity may have been confounded by effects on body temperature.
British Journal of Pharmacology
June 1, 1998
María Isabel Colado, R Granados, Esther O’shea et al.
80 citations
In rats, the drug MDMA ('ecstasy') caused a rapid rise in body temperature (hyperthermia) and, seven days later, damage to serotonin nerve endings in the brain. A low-affinity NMDA receptor blocker, AR-R15896AR, did not prevent the hyperthermia or the long-term loss of serotonin markers in the cortex, striatum, and hippocampus. In contrast, the neuroprotective agent clomethiazole abolished the hyperthermic response and markedly reduced serotonin loss—by about 75% at normal room temperature.
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.
British Journal of Pharmacology
January 1, 2005
Isabel Escobedo, Esther O’shea, Laura Orío et al.
68 citations
MDMA itself does not cause the immediate release of dopamine or serotonin in the mouse brain; instead, peripheral injection of MDMA reduced striatal dopamine and modestly reduced serotonin one hour after the last dose, but direct injection into the striatum did not produce these acute effects. The metabolite HHMA also did not contribute to acute dopamine depletion, as its effects differed from MDMA after peripheral injection. Long-term dopamine loss seven days later was not due to MDMA itself, since only very high intrastriatal doses caused such loss, and HHMA did not alter striatal dopamine after peripheral injection. HHMA crossed the blood–brain barrier but was not detected in brain after peripheral MDMA, suggesting it is metabolized to other active compounds.
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.
British Journal of Pharmacology
June 12, 2006
Esther O’shea, Laura Orío, Isabel Escobedo et al.
57 citations
MDMA (ecstasy) causes long-term damage to serotonin neurons in the rat brain, but measuring serotonin levels alone may overestimate the extent of that damage. In male DA rats given a single dose of MDMA, serotonin content and a marker of serotonin nerve terminals were reduced in the cortex and hippocampus for up to 32 weeks. The activity of the enzyme that makes serotonin was also reduced for 8 weeks but recovered by 32 weeks. Housing rats in a cold environment prevented the loss of nerve-terminal markers but not the drop in serotonin levels, suggesting that the serotonin loss partly reflects enzyme inhibition rather than only neuron death. The damaged neurons did not increase serotonin production to compensate.
Journal of Neurochemistry
January 12, 2010
Elisa Torres, María Dolores Gutiérrez‐lópez, Érika Borcel et al.
44 citations
The drug MDMA ('ecstasy') causes lasting damage to serotonin neurons in rats, partly through inflammation involving microglial activation and release of interleukin-1β. Cannabinoid CB2 receptors, which increase in microglia shortly after MDMA, can help control this inflammation. Giving rats a CB2 receptor agonist (JWH-015) before and after MDMA reduced microglial activation and interleukin-1β release, and slightly lessened the damage to serotonin neurons. Activating CB2 receptors thus partially protects against MDMA's neurotoxic effects.
Pharmacology & Toxicology
June 1, 1999
María Isabel Colado, Raquel Ena María Granados, Esther O’shea et al.
26 citations
A single dose of the recreational drug MDEA ("eve") given to Dark Agouti rats caused an acute, dose-dependent rise in body temperature. The peak hyperthermia from 35 mg/kg of MDEA matched that from 15 mg/kg of MDMA ("ecstasy"). Seven days later, MDMA caused a 50% loss of serotonin and its metabolite in the cortex, hippocampus, and striatum, indicating neurotoxic damage to serotonin nerve endings. MDEA at the highest dose produced only a 20% loss in cortex and hippocampus and no loss in striatum, with weak dose dependence. Neither drug altered striatal dopamine. MDEA had about half the potency of MDMA for hyperthermia and one-quarter the potency for serotonin neuron degeneration.