Vaccine Effects on Fetal Nicotine Exposure in Rats

描述（由申请人提供）：本申请的目的是研究母体接种尼古丁疫苗对大鼠妊娠期给药尼古丁的药代动力学、神经化学后果和行为后遗症的影响。怀孕期间吸烟与广泛的新生儿不良结局有关。动物实验数据有力地表明尼古丁是致畸物，是导致这些不良后果的因素之一。最近有研究表明，成年雄性大鼠接种尼古丁疫苗可大大减少急性或慢性给药尼古丁在大脑和其他器官中的分布。初步数据表明，雌性大鼠接种疫苗也可以减少妊娠期给药尼古丁在胎儿大脑中的分布。这项拟议的研究将探讨疫苗接种改变尼古丁在胎儿体内分布的机制，以及在不同剂量条件下这种影响的程度和后果。尼古丁在怀孕大鼠体内的药代动力学也将被研究，以更好地了解胎儿尼古丁暴露的决定因素。需要验证的具体假设是：1)母亲接种疫苗减少了妊娠期间使用各种临床相关的急性和慢性给药方案给药的尼古丁在胎儿大脑中的分布。2)通过两种互补机制保护胎儿大脑免受妊娠期尼古丁暴露；减少未结合的尼古丁分布到胎儿，以及母体抗体转移到胎儿，然后结合和隔离胎儿血清中的尼古丁，3)疫苗接种减弱了与妊娠期慢性尼古丁暴露相关的胎儿脑c-fos mRNA表达的增加，4)疫苗接种减弱了与妊娠期尼古丁暴露相关的新生儿运动活动的增加，5)尼古丁清除率在未怀孕的女性中低于男性。但女性在怀孕期间会增加。这些免疫学、药代动力学、神经化学和行为学数据将被整合起来，以帮助了解疫苗接种改变胎儿尼古丁分布的机制，以及疫苗接种减少妊娠期尼古丁暴露致畸效应的临床潜力。

DESCRIPTION (provided by applicant): 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.