EFFECTS OF COCAINE AND COCAINE METABOLITES ON MOUSE DEVELOPMENT IN-VITRO

The use of cocaine use has been associated with adverse developmental effects in humans, and cocaine administration produces developmental t oxicity in animal models. However, whether the adverse effects produce d during organogenesis are due directly to the effects of cocaine or i ts metabolites remains to be established. This study was therefore und ertaken to compare the morphological effects of cocaine and its metabo lites, ecgonine, benzoylecgonine (BE) and ecgonine methyl ester (EME) in whole embryo culture (WEC) using early somite stage ICR mice. Cocai ne produced a concentration-dependent induction of defects including e ffects on craniofacial development such as neural tube closure defects (NTDs). Concentrations of cocaine of 51.4 mu M or more produced dysmo rphogenesis and 100% of the embryos exhibited NTDs at 441 mu M. EME al so induced defects at concentrations of 400 mu M or above. Neither ecg onine nor BE altered embryogenesis at concentrations of 2000 mu M or l ess. The incidence of cocaine-induced NTDs was dependent on the length of exposure to cocaine. At 294 mu M, exposures of 3 hr or more were r equired to alter development when evaluated at the end of a 24-hr cult ure period. Lower cocaine concentrations required longer exposure peri ods (6 or 12 hr) to produce dysmorphogenesis. The incidence of NTDs ap pears to follow the area under the concentration time curve and is not solely dependent on the peak cocaine concentration in the medium. Exp osure of conceptuses to a combination of cocaine and EME produced a hi gh incidence of NTDs. These results suggest that the concentration of cocaine or EME required to induce NTDs in vitro is higher than the ter atogenic concentration in vivo. Additionally, the time required for hi gh concentrations of cocaine to induce NTDs is longer than the serum h alf-life of cocaine reported in vivo following a single administration . Thus, NTDs produced by cocaine administration appear not to be due s olely to the effect of cocaine or its metabolites on the conceptus but may involve effects on extraembryonic and/or maternal tissues as well . Published by Elsevier Science Ltd.