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.
British Journal of Pharmacology
March 1, 1993
María Isabel Colado, Tracey K. Murray, A.r. Green
133 citations
Chlormethiazole and dizocilpine prevent neurotoxicity from MDMA (Ecstasy) but not from PCA or fenfluramine in rat brain. MDMA caused about 30% loss of serotonin and its metabolite in cortex and hippocampus; chlormethiazole given before and after MDMA fully protected both regions, while dizocilpine protected only the hippocampus. A single dose of chlormethiazole 20 minutes after MDMA also fully protected the hippocampus but not the cortex and reduced MDMA-induced hyperthermia (about +2.5°C). PCA caused 70% serotonin loss; neither drug prevented this, even when a lower PCA dose caused only 30% loss. Fenfluramine-induced serotonin loss was also not prevented. Both drugs blocked serotonin-related behaviors from all three toxins. The findings suggest different mechanisms underlie neurotoxicity from these amphetamines, and hyperthermia alone does not account for the damage.
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
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.
British Journal of Pharmacology
January 1, 1994
María Isabel Colado, A.r. Green
62 citations
In rats, the drug MDMA ('Ecstasy') caused a 50% loss of serotonin (5-HT) and its metabolite 5-HIAA in the cortex and hippocampus four days later, indicating long-term neurotoxicity. The compounds gamma-butyrolactone and pentobarbitone protected against this loss, while ondansetron did not. MDMA did not significantly affect striatal dopamine levels but slightly reduced DOPAC. Four hours after MDMA, serotonin was depleted by over 80%, and none of the protective drugs altered this initial loss, suggesting protection does not work by blocking serotonin release. Protective compounds may instead inhibit dopamine release in the striatum, as MDMA's neurotoxicity depends on dopamine neurons.
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.