The aim of this proposal is to study the effects of maternal immunization with a nicotine vaccine on the pharmacokinetics, neurochemical consequences, and behavioral sequelae of gestationally administered nicotine in rats. Smoking during pregnancy is associated with a wide range adverse neonatal outcomes. Animal data strongly implicate nicotine as a teratogen and a contributor to these adverse outcomes. It has recently been shown that immunization of adult male rats with a nicotine vaccine can substantially reduce the distribution of acutely or chronically administered nicotine to brain and other organs. Preliminary data suggest that vaccination of female rats can also reduce the distribution of gestationally administered nicotine to fetal brain. The proposed study will address the mechanisms by which vaccination alters nicotine distribution to the fetus, and the magnitude and consequences of this effect under a variety of dosing conditions. The pharmacokinetics of nicotine in the pregnant rat will also be studied to better understand the determinants of fetal nicotine exposure. Specific hypotheses to be tested are that 1) Maternal vaccination reduces the distribution to fetal brain of nicotine administered during gestation using a variety of clinically relevant acute and chronic dosing regimens. 2) Protection of fetal brain from gestational nicotine exposure occurs via two complementary mechanisms; a reduction in unbound nicotine distribution to the fetus, and the transfer of maternal antibody to the fetus which then binds and sequesters nicotine in fetal serum, 3) Vaccination attenuates the increase in fetal brain c-fos mRNA expression associated with chronic gestational nicotine exposure, 4) Vaccination attenuates the increase in neonatal locomotor activity associated with gestational nicotine exposure, and 5) Nicotine clearance is lower in nonpregnant females than in males, but is increased in females during pregnancy. These immunologic, pharmacokinetic, neurochemical and behavioral data will be integrated to help understand the mechanisms by which vaccination alters fetal nicotine distribution, and the clinical potential of vaccination to reduce the teratogenic effects of gestational nicotine exposure.
