EFFECT OF ACUTE MONOAMINE DEPLETION ON 3,4-METHYLENEDIOXYMETHAMPHETAMINE-INDUCED NEUROTOXICITY

The effect of acute, reversible depletion of either serotonin [5-hydro xytryptamine (5-HT)] or dopamine (DA) on the long-term (7-day) decreas e of brain 5-HT content produced after 3,4-methylenedioxymethamphetami ne (MDMA) administration was investigated. The tyrosine hydroxylase in hibitor alpha-methyl-p-tyrosine (alpha-MPT) significantly attenuated t he acute increase in DA efflux produced by MDMA in the striatum as mea sured by in vivo microdialysis. Treatment with alpha-MPT had no effect on MDMA-induced 5-HT release. Alpha-MPT treatment blocked the long-te rm (7-day) depletion of striatal 5-HT content after MDMA administratio n. The tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) c ompletely blocked the acute increase in the extracellular concentratio n of 5-HT produced by MDMA. Although PCPA significantly attenuated the increase in DA efflux produced by MDMA, the effect was small in magni tude. More importantly, treatment with PCPA had no effect on MDMA-indu ced decrease of 5-HT uptake sites in the frontal cortex. These data ar e suggestive that acute depletion of DA but not 5-HT protects against the long-term neurotoxic effects of MDMA on 5-HT axon terminals. In ad dition, these data are supportive of the hypothesis that DA plays a ma jor role in the neurotoxic effects of MDMA.