Multiple drug use among female cocaine abusers is common during pregnancy. Estimates are that 85% of pregnant cocaine users also smoke cigarettes; while use of alcohol, marijuana, amphetamine an tranquilizers decreases between the first and third trimesters, tobacco use does not. Despite the frequency of their combined use, there has been no systematic study of the effects of prenatal cocaine and nicotine exposure. However, use of either drug alone during pregnancy is linked with pregnancy complications, impaired growth and subtle behavioral abnormalities, maternal smoking is also a marker variable for long-term intellectual impairment. The proposed research will determine the behavioral sequelae of prenatal exposure to cocaine and nicotine, either alone or in combination, in offspring using a rat model developed in our laboratory. The working hypothesis is that exposure of the developing brain to non-teratogenic doses of these drugs will disrupt the structural and functional organization of the CNS, which in turn will alter behavior in the offspring. The model involves the daily subcutaneous administration of 20 mg/kg of cocaine and/or 5 mg/kg of nicotine by osmotic pump on gestation days (GD) 8 through 21. Both pair-fed and saline-treated dams will serve as controls. Plasma levels of cocaine, nicotine and their major metabolites will be determine in dams on GD 15 and mothers and pups at birth; dopamine and DOPAC levels will be assayed in several brain region in offspring at various ages. Using a split-litter design, males and females from the 5 prenatal treatment conditions will be tested in a variety of behavioral paradigms. A longitudinal (from 1 week to 15 months of age] approach will be used to: 1) identify the behavioral domains (cognitive, emotional/motivational and motor) affected by prenatal cocaine and nicotine exposure; 2) determine whether combined drug exposure exacerbates or ameliorates the behavioral effects of either drug alone; 3) investigate whether these changes represent a delay in the rat of development, a later appearing alteration in functional capacity of the adult, or an induction of premature senescence; and 4) assess the possibility of gender-specific effects. These experiments will provide some of the first longitudinal data on the effects of prenatal exposure to cocaine and/or nicotine on both male and female offspring, and should begin to establish a consensus about the nature of the behavioral abnormalities produce by gestational exposure to these two drugs. The use of a large battery of behavioral tests, and the choice of the prenatal exposure window and drug doses most frequently used will allow for the replication and extension of the work of several laboratories and facilitate the resolution of conflicting findings regarding the effects of prenatal exposure to either drug alone. As the behaviors targeted also reflect cognitive and/or performance deficits reported in the clinical literature, the outcome of this research may serve as a guideline for determining the relative risks of combined use of these two drugs during pregnancy to the offspring. The identification of deficits as transient of long-term and the domains affected may impact the choice of treatment options.
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