Vaccine Effects on Fetal Nicotine Exposure in Rats

描述（由申请方提供）：本提案的目的是研究母体接种尼古丁疫苗对大鼠妊娠期给予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不良新生儿结局相关。动物数据强烈暗示尼古丁是一种致畸剂，是这些不良结局的促成因素。最近的研究表明，用尼古丁疫苗对成年雄性大鼠进行免疫接种，可以显著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减少妊娠期间给予的尼古丁在胎仔大脑中的分布。拟议的研究将讨论疫苗接种改变胎儿尼古丁分布的机制，以及在各种给药条件下这种影响的程度和后果。还将研究妊娠大鼠中尼古丁的药代动力学，以更好地了解胎儿尼古丁暴露的决定因素。待检验的具体假设为：1）母体接种可减少妊娠期间使用各种临床相关急性和慢性给药方案给予的尼古丁在胎仔脑中的分布。2)保护胎儿大脑免受妊娠期尼古丁暴露通过两种互补机制发生;未结合的尼古丁分布到胎儿的减少，以及母体抗体转移到胎儿，然后结合并隔离胎儿血清中的尼古丁，3）疫苗接种减弱了与慢性妊娠期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）未妊娠女性的尼古丁清除率低于男性，但妊娠期间女性的尼古丁清除率增加。这些免疫学、药代动力学、神经化学和行为学数据将被整合，以帮助理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作用的临床潜力。

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.