No 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.

No abstract

It has been suggested that methamphetamine (METH)-induced neurotoxicity requires the activation of both dopamine (DA) and glutamate (GLU) systems. To investigate the possibility that METH-induced increases in extracellular GLU, as measured by in vivo microdialysis [Nash and Yamamoto (1992) Brain Res., 581:237-243], arise from neuronal stores, postembedding immunogold electron microscopy was used to measure the density of presynaptic GLU immunoreactivity within the striatum, the shell of the nucleus accumbens, and the motor cortex. Rats were treated with METH (5 mg/kg), or an equivalent volume of saline (SAL), every 2 h for a total of four injections. No ultrastructural evidence of terminal degeneration was observed. Significant decreases in the density of nerve terminal GLU immunolabeling occurred 12 h following METH administration within the primary motor cortex and the ventrolateral caudate/putamen, and a trend towards depletion was seen within the dorsolateral caudate/putamen. Although GLU immunolabeling within the shell of the nucleus accumbens was unaffected, DA content was decreased in all regions examined 1 week following METH treatment. The lack of degeneration, coupled with a partial recovery of DA levels, suggests that moderate doses of METH may inhibit DA biosynthesis without widespread terminal loss. Furthermore, METH administration results in a decrease in presynaptic GLU that correlates both temporally and anatomically with delayed GLU overflow, suggesting that neuronally derived GLU may play a role in METH-induced neurotoxicity. However, there does appear to be a dissociation between DA loss and altered GLU immunocytochemistry within the nucleus accumbens.

No abstract