Vaccine Effects on Fetal Nicotine Exposure in Rats

描述(申请人提供)：这项建议的目的是研究尼古丁疫苗母体免疫对孕期服用尼古丁的大鼠的药代动力学、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有关。动物数据强烈表明尼古丁是致畸剂和这些不利结果的贡献者。最近有研究表明，成年雄性大鼠接种尼古丁疫苗可以显著减少急性或长期给予尼古丁到大脑和其他器官的分布。初步数据表明，给雌性大鼠接种疫苗还可以减少孕期给药的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中分布的机制，以及在各种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。需要测试的具体假设是：1)母亲接种疫苗减少了在怀孕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)通过两种互补的机制保护胎儿大脑免受孕期尼古丁暴露的影响：减少游离尼古丁在胎儿体内的分布，并将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)接种疫苗减缓与慢性妊娠尼古丁暴露相关的胎儿脑c-FOS mRNA表达的增加；4)接种疫苗减缓与妊娠尼古丁暴露相关的新生儿运动活动的增加；5)非怀孕女性的尼古丁清除量低于男性，但在怀孕期间女性的尼古丁清除量增加。这些免疫学、药代动力学、神经化学和行为数据将被整合在一起，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尼古丁暴露的致畸影响的临床潜力。

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.