The cytotoxic effects of retinoids on neuroblastoma cells at various times during electrophysiological differentiation were evaluated. We used N1E-115, a clone of the murine neuroblastoma C1300 derived from the neural crest, and three retinoids : vitamin A (retinol), all-trans retinoic acid (tretinoin), and 13-cis-retinoic acid (isotretinoin). Differentiating N1E-115 cells exposed to retinoids at an isotretinoin EC(50) of 16 mu M exhibited the greatest vulnerability in terms of cell death during a period (8 to 10 days) that was previously found to be the most sensitive for induction of gross malformations in rodents. This finding suggested possible similarities between the in vivo and in vitro retinoid mechanism(s) of action. The greatest period of vulnerability to retinoid cytotoxicity was also found to coincide with the rapid resting membrane potential (V-m) development period, suggesting a linkage between neuronal V-m and/or electrical excitability development and vulnerability to retinoid cytotoxicity.