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

Abstract

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 longterm 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.

3,4-Methylenedioxymethamphetamine Produces Glycogenolysis and Increases the Extracellular Concentration of Glucose in the Rat Brain

“…Also consistent with a role of hyperthermia in the MDMA-induced alteration in energy regulation is the finding that the administration of MDMA via reverse dialysis into the striatum did not alter the extracellular concentration of glucose, whereas a significant increase was observed following the systemic administration of MDMA. Although the concentration of MDMA (100 M) perfused into the striatum is sufficient to evoke dopamine and 5-HT release comparable with that produced by the systemic administration of the drug, the local perfusion of MDMA does not produce hyperthermia (Nixdorf et al, 2001). Thus, there appears to be an association between the propensity of MDMA to evoke hyperthermia and induce glycogenolysis.…”

“…The concomitant administration of MDMA and the mitochondrial inhibitor malonate into the striatum has been shown to cause a significant reduction in 5-HT tissue concentration, whereas the local administration of either drug alone was ineffective (Nixdorf et al, 2001). Moreover, the administration of MDMA as well as methamphetamine causes a rapid and transient inhibition of mitochondrial function (Burrows et al, 2000).…”

Evidence for the Involvement of Nitric Oxide in 3,4-Methylenedioxymethamphetamine-Induced Serotonin Depletion in the Rat Brain

“…In addition, the effects of NOS inhibitors or a peroxynitrite decomposition catalyst on the depletion of dopamine and 5-HT elicited by the intrastriatal administration of malonate, a mitochondrial inhibitor, together with MDMA were examined. The combination of malonate and MDMA has been shown to deplete striatal dopamine and 5-HT without producing hyperthermia (Nixdorf et al, 2001), thereby obviating concern for the interaction of NOS inhibitors and MDMA on body temperature. Finally, the effect of MDMA on the generation of nitric oxide and the formation of nitrotyrosine in the striatum also was determined.…”

Chronic Stress Enhances the Corticosterone Response and Neurotoxicity to +3,4-Methylenedioxymethamphetamine (MDMA): The Role of Ambient Temperature

“…The prevention of MDMA-induced oxidative stress with antioxidants or through NO synthase inhibition blocks 5-HT depletions without affecting hyperthermia (Quinton and Yamamoto, 2006), suggesting oxidative stress is a consequence of hyperthermia. Coadministration of MDMA and the mitochondrial complex II inhibitor malonate produces a DA depletion in striatum (Nixdorf et al, 2001), implicating enhanced oxidative stress as a cause of DA depletions in stressed rats. Thus, the augmented hyperthermic response to MDMA in stressed rats may enhance 5-HT depletions and produce a DA depletion via enhanced production of metabolic and oxidative stress.…”