Alcohol abuse during pregnancy is recognized as a significant risk factor to normal fetal growth and development, and alcohol is considered to be a potent teratogenic agent in both humans and animals. Given that alcohol frequently is used concomitantly with other drugs of abuse by pregnant women, it is important to know how the combined use of alcohol and other drugs of abuse affect alcohol's teratogenic effects. The """"""""other"""""""" drug of abuse this project will focus on is cocaine, since its use by pregnant women has increased dramatically in the last decade. In Series I, an established mouse model of alcohol-induced birth defects will be employed. Studies are designed to evaluate the effect of combined alcohol and cocaine administration (either chronically or acutely) on pregnancy outcome in C57BL/6J mice. The primary dependent variables will include the effect on fetal weight, Utter size, and type and number of birth defects. The studies in Series II and III take this research one step further. In Series II, the C57BL/6J mouse model system will be used to measure the effects of concomitant alcohol and cocaine administration on alterations in the vasoactive prostaglandins (thromboxane and prostacyclin) which regulate placental blood flow. Since both alcohol and cocaine have been shown to decrease intrauterine and placental blood flow, alterations in the vasoactive prostaglandins or their """"""""balance"""""""" might be a common site where concomitant alcohol and cocaine exposure may have an interactive effect. Studies manipulating endogenous thromboxane and prostacyclin levels in vivo are proposed, as well. A unique aspect of this proposal is that in Series III, we propose to use the human placenta and human umbilical artery to address the effect of concomitant alcohol and cocaine exposure on thromboxane and prostacyclin production or levels. Thus, we will utilize both animal and human tissue to address a potential mechanism for the co-teratogenicity of alcohol and cocaine. In summary, the proposed research will begin to fill a void in the literature regarding the effect of concomitant alcohol and cocaine administration on pregnancy outcome. Moreover, it win begin to address issues related to a mechanism of action which might be able to explain at least some of the teratogenic effects of the drug combination. Since there is virtually no information in the literature on this topic, the results generated will be of major significance to the prenatal field.
