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

The acute and long-term effects of the local perfusion of 3,4-methylenediox ymethamphetamine (MDMA) and the interaction with the mitochondrial inhibito r malonate (MAL) were examined in the rat striatum. MDMA, MAL or the combin ation 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 wa s 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 contras t to MDMA, produced only longterm depletion of DA. The combined perfusion o f MDMA/MAL synergistically increased the release of DA and 5-HT and produce d 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 f or bin-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.