Methamphetamine neurotoxicity involves vacuolation of endocytic organelles and dopamine-dependent intracellular oxidative stress

• DOI: 10.1523/jneurosci.14-04-02260.1994
• Publication Date: 2018-04-02T14:55:39Z
• Authors: JF Cubells; S Rayport; G Rajendran; D Sulzer
• Keywords: Neurotoxicity; Excitotoxicity

Methamphetamine (MA) produces selective degeneration of dopamine (DA) neuron terminals without cell body loss. While excitatory amino acids (EAAs) contribute to MA toxicity, terminal loss is not characteristic excitotoxic lesions nor excitotoxicity for DA fibers; rather, EAAs may modulate MA-induced turnover, suggesting that DA-dependent events play a key role in neurotoxicity. To examine this possibility, we used postnatal ventral midbrain cultures maintained under continuous EAA blockade. As vivo, caused neurite but minimal death. We found vacuologenic weak base induces swelling endocytic compartments; also blebbing the plasma membrane. However, these morphological changes occurred MA-treated lacking neurons. Therefore, while collapse endosomal and lysosomal pH gradients vacuolation neurotoxicity, does explain degeneration. Alternatively, could exert its neurotoxic effects by collapsing synaptic vesicle proton redistributing from vesicles cytoplasm. This cause formation DA-derived free radicals reactive metabolites. test whether oxidative stress within living neurons, 2,7-dichlorofluorescin diacetate (DCF), an indicator intracellular hydroperoxide production. dramatically increased number DCF-labeled cells cultures, which contain about 30% nucleus accumbens do In DDF labeling was localized axonal varicosities, blebs, organelles. These results suggest redistributes reducing environment extravesicular oxidizing environments, thus generating oxygen metabolites neurons trigger