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.
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.
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.