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Journal of Neuroscience, Vol 14, 2260-2271, Copyright © 1994 by Society for Neuroscience
Methamphetamine neurotoxicity involves vacuolation of endocytic organelles and dopamine-dependent intracellular oxidative stress
JF Cubells, S Rayport, G Rajendran and D Sulzer
Department of Psychiatry, Columbia University, New York, New York 10032.
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 of
excitotoxic lesions nor is excitotoxicity selective for DA fibers; rather,
EAAs may modulate MA-induced DA turnover, suggesting that DA- dependent
events play a key role in MA neurotoxicity. To examine this possibility, we
used postnatal ventral midbrain DA neuron cultures maintained under
continuous EAA blockade. As in vivo, 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 induces blebbing of the
plasma membrane. However, these morphological changes occurred in
MA-treated cultures lacking DA neurons. Therefore, while collapse of
endosomal and lysosomal pH gradients and vacuolation may contribute to MA
neurotoxicity, this does not explain selective DA terminal degeneration.
Alternatively, MA could exert its neurotoxic effects by collapsing synaptic
vesicle proton gradients and redistributing DA from synaptic vesicles to
the cytoplasm. This could cause the formation of DA-derived free radicals
and reactive metabolites. To test whether MA induces oxidative stress
within living DA neurons, we used 2,7-dichlorofluorescin diacetate (DCF),
an indicator of intracellular hydroperoxide production. MA dramatically
increased the number of DCF-labeled cells in ventral midbrain cultures,
which contain about 30% DA neurons, but not in nucleus accumbens cultures,
which do not contain DA neurons. In the DA neuron cultures, intracellular
DDF labeling was localized to axonal varicosities, blebs, and endocytic
organelles. These results suggest that MA redistributes DA from the
reducing environment within synaptic vesicles to extravesicular oxidizing
environments, thus generating oxygen radicals and reactive metabolites
within DA neurons that may trigger selective DA terminal loss.
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