MDMA is a unique psychostimulant that continues to be a popular drug of abuse. It is well documented that MDMA produces persistent reductions in markers of 5-HT axon terminals in rodents, as well as humans. To date, there has been little recognition of potential MDMA neurotoxicity to neuronal populations beyond 5-HT axon terminals in brain regions, such as the hippocampus, in which damage may account for the neurologic/cognitive effects associated with repeated exposure to MDMA. In the present study, we examined the hypothesis that MDMA produces glutamate-dependent damage to GABAergic neurons, as assessed from GAD67-positive neurons in the hippocampus, which results in an increase in seizure susceptibility. Repeated exposure to MDMA (3x10mg/kg, ip) resulted in a reduction of approximately 35- 55% in the number of GAD67 positive cells in the dentate gyrus, CA1, and CA3 regions. These reductions were significantly less in animals treated with MK-801 (an NMDA antagonist) or ceftriaxone (an inducer of GLT-1). In further support of overall hypothesis is the finding that MDMA increases the extracellular concentration of glutamate; this glutamate response was diminished in rats treated previously with either ceftriaxone or SC-51089 (a prostanoid EP1 receptor antagonist). Repeated administration of MDMA also resulted in an increased susceptibility to kainic acid-induced seizures that persisted for at least 30 days following MDMA treatment. Kainic acid (8 mg/kg, sc) produced seizures in approximately 20% of control animals, whereas approximately 85% of MDMA-treated animals exhibited kainic acid-induced seizures. The MDMA-induced increase in seizure susceptibility was not evident in rats treated with MK-801, ceftriaxone, or SC-51089. These findings substantiate a role for glutamate in the MDMA-induced damage to GABAergic neurons within the hippocampus and the subsequent increase in seizure susceptibility. Additional evidence is provided to support the hypothesis that prostaglandin signaling is necessary for the MDMA-induced increase in glutamate and the ultimate increase in seizure susceptibility.