Cocaine is one of the most widely abused drugs in the United States, resulting in thousands of overdose deaths every year. However, relatively little is known about the molecular mechanisms underlying the drug’s toxic effects.
Researchers used biochemical and microscopy techniques to assess how cocaine kills neurons in the brain. Compared with exposure to a control substance, cocaine exposure increased and depleted levels of the proteins LC3-II and p62, respectively, stimulated the formation of double-membrane vesicles, caused the border of the cell nucleus to curve inward, and triggered cell death.
These observations demonstrate that the toxic effects of cocaine are mediated by autophagy—a process that degrades cellular components and can kill cells.
Moreover, treatment of neurons with the drug CGP3466B, which prevents nitrosylation of the GAPDH enzyme, abolished cocaine-induced autophagy. The findings demonstrate that cocaine activates the nitric oxide-GAPDH signaling pathway to trigger autophagy in neurons.
Because CGP3466B strongly suppresses nitric oxide-GAPDH signaling at low doses and has not produced serious side effects in past clinical trials for neurodegenerative disorders, this drug or other autophagy-inhibiting agents may prove safe and effective for treatment of cocaine abuse, according to the authors.