Conclusions

Substantial evidence supports the hypothesis that an increase in extracellular glutamate following MA administration is an obligatory step in the cascade of events culminating in striatal DA terminal loss. Several different mechanisms may contribute to this rise in extracellular glutamate, including a circuit-mediated increase in corticostriatal activity, a decrease in glutamate uptake into glia, and an increase in vesicular release following disruption of the membrane potential via a loss of Na+/K+-ATPase activity. Increased glutamate overflow likely contributes to the toxicity of amphetamines by initiating an excitotoxic response. Together, MA-mediated DA release and NMDA receptor activation can lead to the formation of intracellular reactive oxygen species and inhibition of metabolic function. Both oxidative and metabolic stress have been implicated in mediating the damage to DA terminals following MA administration, and substrates that attenuate the consequences of such stressors (antiox-idants, free-radical scavengers, or substrates for the electron-transport chain) are neuroprotective. Additional evidence points to an inherent vulnerability of DA terminals to metabolic stress when compared with 5-HT systems, suggesting that factors which mediate the neurotoxic effect of MA on DA and 5-HT terminals may be substantially different.

Although the toxicity of MA was first recognized almost 30 yr ago (164,165), the mechanisms culminating in DA loss are still under investigation. Recent evidence of DA terminal dysfunction in human MA abusers (11,12,166) indicates that MA abuse may have lasting consequences. It is not known if MA abuse is a risk factor in Parkinson's disease. Nevertheless, the possibility exists that MA-induced damage to the nigrostriatal DA system could result in an earlier onset of symptoms in individuals predisposed to develop Parkinson's disease. Further clinical and preclinical studies are obviously necessary to elucidated the risks, consequences, and treatment of stimulant-induced damage to the nigrostriatal DA system. A more basic understanding of factors that influence changes in the dopamin-ergic and serotonergic systems following MA exposure will hopefully lead to novel therapies designed to reverse or attenuate the excitotoxic, metabolic, and oxidative effects of this abused drug.

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