LONG-LASTING MICRENCEPHALY FOLLOWING EXPOSURE TO COCAINE DURING THE BRAIN GROWTH SPURT IN THE RAT

In utero exposure to cocaine has been shown to produce somatic and beh avioral effects. As microencephaly is often present in children born f rom cocaine-addicted mothers, aim of the present study was to develop an animal model for cocaine-induced microencephaly. Rats were treated with cocaine (20, 30 or 50 mg/kg/day, s.c., each dose divided in two e qual doses given 3 h apart) from postnatal day 4 through 10. None of t he doses had any effect on growth, however, at 50 mg/kg, cocaine cause d a significant decrease in brain weight, measured on day 12. The effe ct of cocaine was similar in male and female rats, and microencephaly was still present in 45-day-old animals. When the same dose of cocaine was given as a single daily injection, long-lasting microencephaly wa s also present, but it was accompanied by a decrease in body weight an d significant toxicity. Ethanol (4 g/kg), used as a positive control, also caused microencephaly without affecting body weight, but, differe ntly from cocaine, its effect was more pronounced in female animals. B lood and brain levels of cocaine and its metabolites norcocaine and be nzoylecgonine were measured by HPLC during treatment (postnatal day 8) . After administration of the 50 mg/kg dose, concentrations of cocaine were 1.92 mu g/g in brain and 0.94 mu g/ml in blood. These levels are encountered in cases of cocaine overdoses and have been found in meco nium of newborns from crack-addicted mothers. As cocaine and norcocain e have been shown to inhibit in vitro muscarinic receptor-stimulated p hosphoinositide metabolism, which may be associated with ethanol's ind uced microencephaly, this biochemical response was measured in cerebra l cortex from cocaine-treated rats. A dose-dependent inhibition of car bachol-stimulated inositol phospholipid metabolism was observed. In su mmary, these experiments establish a rodent model for cocaine-induced microencephaly, which should be useful to further investigate this asp ect of the developmental neurotoxicity of cocaine and its underlying m echanism(s).