Enhancement of 3,4-methylenedioxymethamphetamine neurotoxicity by the energy inhibitor malonate.

The acute and long-term effects of the local perfusion of 3,4-methylenedioxymethamphetamine (MDMA) and the interaction with the mitochondrial inhibitor malonate (MAL) were examined in the rat striatum. MDMA, MAL or the combination of MAL with MDMA was reverse dialyzed into the striatum for 8 h via a microdialysis probe while extracellular dopamine (DA) and serotonin (5-HT) were measured. One week later, tissue immediately surrounding the probe was assayed for DA and 5-HT tissue content. Local perfusion of MDMA increased DA and 5-HT release but did not produce long-term depletion of DA or 5-HT in tissue. Malonate also increased both DA and 5-HT release but, in contrast to MDMA, produced only long-term depletion of DA. The combined perfusion of MDMA/MAL synergistically increased the release of DA and 5-HT and produced long-term depletion of both DA and 5-HT in tissue. These results support the conclusion that DA, compared with 5-HT, neurons are more susceptible to mitochondrial inhibition. Moreover, MDMA, which does not normally produce DA depletion in the rat, exacerbated MAL-induced DA depletions. The effect of MDMA in combination with MAL to produce 5-HT depletion suggests a role for bio-energetic stress in MDMA-induced toxicity to 5-HT neurons. Overall, these results highlight the importance of energy balance to the function of DA and 5-HT neurons and to the toxic effects of MDMA.