Memantine prevents MDMA-induced neurotoxicity

MDMA (ecstasy) is an illicit drug causing long-term neurotoxicity. Previous studies demonstrated the interaction of MDMA with alpha-7 nicotinic acetylcholine receptor (nAChR) in mouse brain membranes and the involvement of alpha-7 nicotinic acetylcholine receptors (nAChR) in dopaminergic neurotoxicity induced by MDMA in mice. The aim of the present study was to investigate the utility of memantine (MEM), an alpha-7 nAChR antagonist used for treatment of Alzheimer's disease patients, to prevent neurotoxicity induced by MDMA in rats and the oxidative effect of this amphetamine derivative in mice striatal synaptosomes.In isolated mouse striatal synaptosomes (an in vitro model of MDMA neurotoxicity of dopaminergic origin), MDMA (50 μM)-induced reactive oxygen species (ROS) production that was fully inhibited by MEM (0.3 μM). This effect of MEM was fully prevented by PNU 282987 (0.5 μM), a specific agonist of alpha-7 nAChR. The preventive effect of MEM on this oxidative effect can be attributed to a direct antagonism between MDMA (acting probably as agonist) and MEM (acting as antagonist) at the alpha-7 nAChR.In Dark Agouti rats (an in vivo model of MDMA neurotoxicity of serotonergic origin), a single dose of MDMA (18 mg/kg) induced persistent hyperthermia, which was not affected by MEM pre-treatment. [3H]Paroxetine binding (a marker of serotonergic injury) was measured in the hippocampus of animals killed at 24 h and 7 days after treatment. MDMA induced a significant reduction in [3H]paroxetine binding sites at both times of sacrifice that was fully prevented by pre-treatment with MEM.Since previous studies demonstrate that increased glutamate activity is not involved in the neurotoxic action of MDMA, it can be concluded that the effectiveness of MEM against MDMA-induced neurotoxicity would be the result of blockade of alpha-7 nAChR, although an indirect mechanism based on the interplay among the various neurotransmission systems leading to an increase in basal acetylcholine release should also be taken into account.