Cocaine induces apoptosis in cortical neurons of fetal mice.

Exposure of fetal mouse brain cocultures to cocaine results selectively in the loss of neurites followed by neuronal death. By using enriched neuronal cultures, we here demonstrate that disappearance of neurons, when cultured with cocaine, is caused by apoptosis, based on (1) characteristic morphology of apoptotic nuclei at the level of neurons but not of glial cells by optic microscopy, and on total cell pellets by electron microscopy; (2) fragmentation of total DNA with a typical "ladder" pattern on agarose gels; (3) extensive in situ DNA fragmentation labeling (TUNEL method); and (4) prevention of cell loss by cycloheximide. The major metabolites of cocaine have no detectable effects on neurons, indicating that apoptosis is due to cocaine itself. Inappropriate neuronal apoptosis in cocaine-exposed fetal brain could perturb the neurodevelopmental program and contribute to the quantitative neuronal defects that are too frequently reported in the offspring of cocaine-abusing pregnant women.