In humans, 3,4-methylenedioxymethamphetamine (MDMA) induces stimulant and psychedelic effects, probably giving rise to the recent surge in its popularity as a drug of abuse. In animals, MDMA is a selective CNS serotonergic (5HT) neurotoxin. Because of increasing concerns that MDMA might cause serotonergic damage in humans the drug is currently the focus of intense scientific study. Despite these efforts, however, its toxic mechanism of action remains uncertain. IN proposed research explores a novel hypothesis regarding this mechanism. In addition to MDMA, hypoxemia or hypoglycemic states also produce CNS neuronal cell damage. Evidence indicates that this neuronal damage is produced by a massive influx of extracellular calcium, gated by the activation of receptor-operated (N-methyl-D-aspartate [NMDA] receptor) and voltage-sensitive calcium channels. Preliminary experiments show that the NMDA receptor and voltage-gated calcium channel antagonists, dextrorphan (DEX), dextromethorphan (DEXTR), flunarizine, and cinnarizine also block the neurotoxic effects of MDMA in rats. The findings raise the possibility that calcium influx, possibly mediated via an MDMA-induced activation of glutamatergic pathways, plays an important role in the neurotoxic mechanism of action of MDMA. The proposed research will test this hypothesis by: 1) determining if glutamatergic systems play an important role in the neurodegenerative effects of MDMA, as assessed by a pharmacological, neurochemical, electrophysiological, and surgical approach; 2) examining if the neurotoxic effects of MDMA are altered by drugs capable of inhibiting or promoting the influx of extracellular calcium; and 3) exploring whether an activation of intracellular calcium-dependent enzymes provides a mechanism by which MDMA actually produces cell damage. There is growing interest in the use of neurotransmitter-specific neurotoxins to model human neurodegenerative illnesses. Studying the mode of action of selective neurotoxins may provide clues as to the factors that predispose certain neuronal populations to a premature death in such illnesses as parkinson's, huntington's, or alzheimer's disease.
