Repeated doses of MDMA (Ecstasy) cause a delayed and sustained increase in glutamate release in the rat hippocampus. Blocking cyclooxygenase (COX) enzymes, particularly COX-2, with drugs like ketoprofen or nimesulide reduces this glutamate rise, while a COX-1 inhibitor does not. Direct application of prostaglandin E2, a COX product, also raises glutamate levels. Repeated MDMA treatment reduces the number of parvalbumin-positive GABA interneurons in the dentate gyrus, an effect lessened by ketoprofen. However, COX inhibition does not prevent long-term serotonin depletion in the hippocampus. These findings suggest COX activity contributes to MDMA-induced glutamate release and GABA neuron loss but not to serotonin depletion.
Prior exposure to MDMA makes rats vulnerable to stress-induced learning impairments that do not occur with stress alone. Rats pretreated with MDMA and then exposed to mild chronic unpredictable stress seven days later showed impaired learning in the Morris water maze, whereas stress alone did not cause this deficit. MDMA alone increased anxiety-like behavior on the elevated plus maze, but chronic stress alone or combined with MDMA pretreatment did not increase anxiety. The learning impairment was not accompanied by enhanced depletion of the serotonin transporter in the hippocampus, suggesting the effect involves mechanisms beyond serotonin transporter loss.