DNA fragmentation and oxidative stress in the hippocampal formation: A bridge between 3,4-methylenedioxymethamphetamine (ecstasy) intake and long-lasting behavioral alterations

Intake of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) in humans leads to marked behavioral alterations. In a recent paper, we demonstrated that chronic MDMA intake produces a latent hippocampal hyperexcitability that parallels a reduced threshold for limbic seizures and a slowing of electroencephalographic activity. These phenomena suggest an alteration in hippocampal function. So far, only a few studies have focused on the hippocampal formation as a potential target for the effects induced by MDMA. In this study we sought to evaluate whether the intrinsic cells of the hippocampus might be modified chronically by ecstasy intake. In particular, we examined whether administration of MDMA, at doses producing hippocampal hyperexcitability also produces rearrangements of DNA strands measured by the comet assay. We found that MDMA, at very low doses, comparable with those self-administered by humans, produces acute oxidative stress and DNA single and double-strand breaks, which persist together withlong-lasting metabolic changes in the hippocampal formation. These persisting effects are accompanied by behavioral sensitization, reduced seizure threshold and long-lasting slowing of electroencephalographic activity, and hyperexcitability of the hippocampus, without affecting the basal ganglia. The present data indicate that the intake of very low doses of MDMA, comparable to those consumed by humans, produces selective hippocampal alterations which may underlie cognitive impairment and seizure susceptibility.