EFFECTS OF COCAINE ADMINISTRATION DURING EARLY ORGANOGENESIS ON PRENATAL DEVELOPMENT AND POSTNATAL-GROWTH IN MICE

Cocaine use has been associated with adverse developmental effects in humans. However, clinical reports both confirm and deny an association between cocaine use and malformations. Similarly, differences in spec ies and strain, as well as route and timing of cocaine administration, have added to the difficulties in determining the teratogenicity of c ocaine in animal models. This study was undertaken to compare the effe cts of dose, route, and timing of cocaine administration in ICR mice d uring early organogenesis, A single intraperitoneal (ip) administratio n of cocaine (greater than or equal to 60 mg/kg) on Day 9 of gestation (plug day = 1) produced maternal lethality. The predominant developme ntal effect of cocaine administration was an increase in the percentag e of litters exhibiting an enlarged renal pelvis. Despite a high incid ence of affected pups at these doses, the enlargement was not severe, These results, in agreement with previous reports, provide further evi dence that the developing urogenital system is sensitive to cocaine ad ministration, When cocaine was administered using a subcutaneous route , pup weights were greater and the incidence of enlarged renal pelvis was lower than when an ip route was used. To better mimic human binge cocaine abuse, the toxicity of a ''split dose'' was determined. A 60 m g/kg dose was administered using one administration of 60 mg/kg, two t reatments of 30 mg/kg, or three administrations of 20 mg/kg with 1 hr separating the treatments. The incidence of enlarged renal pelvis was similar when cocaine was administered as one or two but was decreased when cocaine was administered as three treatments. Both the route and split-dose studies suggest that high-peak serum concentrations are req uired to perturb development. There were no differences in the inciden ce or severity of enlarged renal pelvis when cocaine was administered on Day 8, 9, or 10 or on all 3 days of gestation. This suggested that the increase in enlarged renal pelvis may not be a specific teratogeni c effect of cocaine administration but may be a delay of normal develo pment induced by cocaine exposure during this early period of organoge nesis. To address this hypothesis, cocaine was administered on Day 9 u sing an ip route and the pups were allowed to be naturally born. In pu ps whose mothers received cocaine there was an increase in postnatal d eaths and a trend toward a reduction in pup body weight/litter at Post natal Day 21, However, when renal morphology was assessed on Postnatal Day 21 no abnormal kidneys were seen. This supports the hypothesis th at enlarged renal pelvis produced by cocaine administration during ear ly organogenesis represents a developmental delay and not a persistent teratogenic defect. These studies suggest that high peak cocaine conc entrations are required to delay normal kidney morphogenesis in mice. (C) 1995 Society of Toxicology