Methamphetamine Neurotoxicity Involves Vacuolation of Endocytic Organelies and Dopamine-Dependent Intracellular Oxidative

Methamphetamine (MA) produces selective degeneration of dopamine (DA) neuron terminals without cell body loss. While excitatory amino acids (EAAs) contribute to MA toxicity, ter-minal loss is not characteristic of excitotoxic lesions nor is excitotoxicity selective for DA fibers; rather, EAAs may mod-ulate MA-induced DA turnover, suggesting that DA-depen-dent events play a key role in MA neurotoxicity. To examine this possibility, we used postnatal ventral midbrain DA neu-ron cultures maintained under continuous EAA blockade. As in viva, MA caused neurite degeneration but minimal cell death. We found that MA is a vacuologenic weak base that induces swelling of endocytic compartments; MA also in-duces blebbing of the plasma membrane. However, these morphological changes occurred in MA-treated cultures lacking DA neurons. Therefore, while collapse of endosoma