Cocaine differentially inhibits neuronal differentiation and proliferation in vitro

The outcome of in utero cocaine exposure is unclear. To determine if cocaine affects neuronal growth and differentiation, we used PC-12 cells, which have a mitogenic response to IGF-I and differentiate into neurons on exposure to nerve growth factor. Differentiation was quantified as neurite extension after a 72-h exposure to 20 ng/ml nerve growth factor (dosage at 50% maximal effectiveness) and cocaine doses ranging from 0.01 to 10 micrograms/ml. The results were 49 +/- 2, 40 +/- 3, 29 +/- 2, 23 +/- 2, and 12 +/- 2% differentiation with respective cocaine concentrations of 0, 0.01, 0.1, 1, and 10 micrograms/ml (P < 0.0001). Cocaine stability studies showed insignificant spontaneous hydrolysis under the conditions of this study. Cocaine did not affect cell viability or number, but had a relatively modest, statistically significant (P < 0.001) inhibitory effect on IGF-I-stimulated thymidine incorporation. The dose-response curves for differentiation vs mitogenic response differed significantly (P = 0.021). Therefore, cocaine inhibition of these processes is probably mediated by different mechanisms, and not caused by generalized toxicity. To our knowledge, this is the first demonstration of cocaine effects on neuronal multiplication and differentiation in vitro. The results suggest in utero exposure may directly impair brain development.