Effects of cocaine and cocaine metabolites on mouse developmentin vitro

The use of cocaine use has been associated with adverse developmental effects in humans, and cocaine administration produces developmental toxicity in animal models. However, whether the adverse effects produced during organogenesis are due directly to the effects of cocaine or its metabolites remains to be established. This study was therefore undertaken to compare the morphological effects of cocaine and its metabolites, ecgonine, benzoylecgonine (BE) and ecgonine methyl ester (EME) in whole embryo culture (WEC) using early somite stage ICR mice. Cocaine produced a concentration-dependent induction of defects including effects on craniofacial development such as neural tube closure defects (NTDs). Concentrations of cocaine of 51.4 mum or more produced dysmorphogenesis and 100% of the embryos exhibited NTDs at 441 mum. EME also induced defects at concentrations of 400 mum or above. Neither ecgonine nor BE altered embryogenesis at concentrations of 2000 mum or less. The incidence of cocaine-induced NTDs was dependent on the length of exposure to cocaine. At 294 mum, exposures of 3 hr or more were required to alter development when evaluated at the end of a 24-hr culture period. Lower cocaine concentrations required longer exposure periods (6 or 12 hr) to produce dysmorphogenesis. The incidence of NTDs appears to follow the area under the concentration time curve and is not solely dependent on the peak cocaine concentration in the medium. Exposure of conceptuses to a combination of cocaine and EME produced a high incidence of NTDs. These results suggest that the concentration of cocaine or EME required to induce NTDsin vitro is higher than the teratogenic concentrationin vivo. Additionally, the time required for high concentrations of cocaine to induce NTDs is longer than the serum half-life of cocaine reportedin vivo following a single administration. Thus, NTDs produced by cocaine administration appear not to be due solely to the effect of cocaine or its metabolites on the conceptus but may involve effects on extraembryonic and/or maternal tissues as well.