Effects of cocaine on rat embryo development in vivo and in cultures

Intraperitoneal injections of 6.25, 12.5, 25, 50, and 100 mumols/kg cocaine into pregnant Sprague-Dawley rats once a day from d 0 to 19 of gestation caused a dose-dependent increase in fetal soft tissue malformations, primarily of the genitourinary tract. At 100 mumols/kg, all implants were lost and three of the five animals died after six to seven injections. At 50 and 100 mumols/kg but not at lower doses, cocaine caused a small but significant decrease in body weight and food intake. Cocaine did not affect mean fetal and placental weights, although it increased the number of runts and edematous fetuses, and did not cause skeletal malformations. After intraperitoneal injection of 50 mumols/kg, the plasma t1/2 of cocaine was 21 +/- 5 min and peak plasma concentration (1682 +/- 260 pmol/mL, measured by HPLC) was achieved in 5-10 min; a lower peak plasma concentration (486 +/- 103 pmol/mL) was achieved in 20-60 min after s.c. injection. Concentrations of dopamine, epinephrine, and norepinephrine in brains of fetuses or newborn pups (less than 12 h old) of cocaine (50 mumols/kg)-treated rats were not significantly elevated. Cocaine injections did not affect gestational duration nor the growth pattern and the locomotor activity of offspring. However, three pups born to one cocaine-treated animal died 20 d after birth. Cocaine inhibited the growth of 10.5-d-old embryos in culture in a concentration-dependent manner and was more toxic than procaine. Approximately 80% of cocaine was metabolized during a 48-h period in embryo culture medium. It is concluded that cocaine possesses teratogenic potential that may be partly independent of maternal toxicity.